Baggrund for Medicinrådets anbefaling vedrørende tildrakizumab som mulig standardbehandling til moderat til svær plaque psoriasis

Transkript

1 Baggrund for Medicinrådets anbefaling vedrørende tildrakizumab som mulig standardbehandling til moderat til svær plaque psoriasis Versionsnr.: 1.0

2 Om Medicinrådet Medicinrådet er et uafhængigt råd, som udarbejder anbefalinger og vejledninger om lægemidler til de fem regioner. Medicinrådet vurderer, om nye lægemidler og nye indikationer kan anbefales som mulig standardbehandling og udarbejder fælles regionale behandlingsvejledninger. Nye lægemidler vurderes i forhold til effekt, eksisterende behandling og pris. Det skal give lavere priser og lægemidler, der er til størst mulig gavn for patienterne. De fælles regionale behandlingsvejledninger er vurderinger af, hvilke lægemidler der er mest hensigtsmæssige til behandling af patienter inden for et terapiområde og dermed grundlag for ensartet høj kvalitet for patienterne på tværs af sygehuse og regioner. Om anbefalingen Anbefalingen er Medicinrådets vurdering af, om omkostningerne ved behandling lægemidlet er rimelige i forhold til lægemidlets kliniske værdi. Lægemidlet vurderes efter Metodehåndbog for Medicinrådets arbejde med at udarbejde fælles regionale vurderinger af nye lægemidlers og nye indikationers kliniske merværdi version 1. Se Medicinrådets metodehåndbog for yderligere information. Dokumentoplysninger Godkendelsesdato Ikrafttrædelsesdato Dokumentnummer Versionsnummer 10. april april Medicinrådet, Publikationen kan frit refereres med tydelig kildeangivelse. Medicinrådet, Dampfærgevej 27-29, 3. th., 2100 København Ø Sprog: dansk Format: pdf Udgivet af Medicinrådet, 10. april 2019 Side 1 af 8

3 Indhold 1 Lægemiddelinformationer Medicinrådets anbefaling Formål Baggrund... 4 Sagsbehandlingstid og proces for Medicinrådets vurdering Medicinrådets vurdering af samlet klinisk merværdi Høring Resumé af økonomisk beslutningsgrundlag Overvejelser omkring alvorlighed/forsigtighed Sammensætning af fagudvalg og kontaktinformation til Medicinrådet Versionslog Bilag... 8 Side 2 af 8

4 1 Lægemiddelinformationer Lægemidlets oplysninger Handelsnavn Generisk navn Firma ATC-kode Virkningsmekanisme Administration/dosis EMA-indikation Ilumetri tildrakizumab Almirall L04AC17 Humaniseret monoklonalt antistof rettet mod interleukin (IL)-23. Subkutan injektion 100 mg i uge 0, 4 og hver 12. uge herefter. Behandling af moderat til svær plaque psoriasis hos voksne ( 18 år), som er kandidater til systemisk behandling. 2 Medicinrådets anbefaling Medicinrådet anbefaler tildrakizumab som mulig standardbehandling til behandling af moderat til svær plaque psoriasis hos voksne, som er kandidater til 2. generations immunmodulerende behandling. Medicinrådet finder, at der er et rimeligt forhold mellem lægemidlets kliniske merværdi og omkostningerne ved behandling med tildrakizumab sammenlignet med dansk standardbehandling. Det kliniske spørgsmål, som ligger til grund for anbefalingen, er som følger: Hvad er den kliniske merværdi af tildrakizumab til voksne patienter med moderat til svær plaque psoriasis, som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisartropati? Side 3 af 8

5 3 Formål Formålet med Baggrund for Medicinrådets anbefaling vedrørende tildrakizumab som mulig standardbehandling til moderat til svær plaque psoriasis er at skabe gennemsigtighed om det materiale, der ligger til grund for Medicinrådets anbefaling. 4 Baggrund I Danmark, som i øvrige dele af verden, får ca. 2-3 % af befolkningen psoriasis i løbet af livet. Psoriasis er en autoimmun, kronisk, inflammatorisk sygdom, hvor plaque psoriasis, også kaldet psoriasis vulgaris, er den mest almindelige (ca. 80 %). Ved udgangen af 2017 var der registreret 2710 patienter, der havde modtaget behandling med 2. generations immunmodulerende lægemidler. Det forventede antal patienter på landsplan er pr. år ca. 100 nye patienter, som er kandidater til 2. generations immunmodulerende behandling. Det drejer sig om psoriasispatienter, der opfylder kriterierne for biologisk behandling, og som ikke har ledgener. Derudover forventes det, at ca. 100 patienter pr. år fejler på et 2. generations immunmodulerende lægemiddel og skal skifte til et andet lægemiddel. Sagsbehandlingstid og proces for Medicinrådets vurdering Medicinrådet modtog den foreløbige ansøgning den 18. september 2018, og protokollen blev sendt til ansøger den 26. oktober Den endelige ansøgning blev modtaget den 19. december Medicinrådet har derfor gennemført vurderingen af tildrakizumab på 16 uger. Den forlængede sagsbehandlingstid skyldes ændringer i sammensætningen af fagudvalget. 5 Medicinrådets vurdering af samlet klinisk merværdi Medicinrådet vurderer, at tildrakizumab til voksne ( 18 år) patienter med moderat til svær plaque psoriasis, som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisartropati, giver: Ingen klinisk merværdi til patienter med moderat til svær plaque psoriasis sammenlignet med guselkumab. Evidensens kvalitet vurderes at være lav. Den kliniske merværdi kan ikke vurderes for subpopulationen af patienter med tidligere behandlingssvigt på biologiske lægemidler generelt. Den kliniske merværdi kan ikke vurderes for subpopulationen af patienter med tidligere behandlingssvigt på biologiske lægemidler med samme target. 6 Høring Ansøger har indsendt høringssvar den 18. marts Ansøger havde ikke bemærkninger til kategoriseringen af klinisk merværdi (bilag 3). Side 4 af 8

6 7 Resumé af økonomisk beslutningsgrundlag Amgros har sammenlignet omkostningerne ved tildrakizumab med alle de behandlinger, der har været betragtet som ligestillede 1. linjebehandlinger (adalimumab, certolizumab pegol, secukinumab, ustekinumab, guselkumab, ixekizumab og brodalumab). Omkostningerne er større ved behandling med tildrakizumab end med det billigste alternativ (adalimumab). På denne baggrund vurderer Amgros, at der ikke er et rimeligt forhold mellem omkostninger og klinisk merværdi. Amgros har vurderet, at ansøgers budgetkonsekvensanalyse er rimelig, og denne estimerer budgetkonsekvenserne til at være ca kr. årligt (AIP-priser). Budgetkonsekvensanalysen antager, at tildrakizumab erstatter lægemidler med samme virkningsmekanisme i behandlingsalgoritmen. Amgros vurderer dog, at det vil være hensigtsmæssigt, at tildrakizumab anbefales som mulig standardbehandling og indplaceres i lægemiddelrekommandationen, så lægemidlet i fremtiden kan konkurrenceudsættes på lige fod med de øvrige 1. linjebehandlinger. Amgros beslutningsgrundlag er baseret på den sundhedsøkonomiske analyse indsendt af ansøger, den indgåede aftale med Almirall om pris for tildrakizumab, samt gældende aftalepris på komparatorer, herunder priser på biosimilære alternativer (se bilag 1 og 2). 8 Overvejelser omkring alvorlighed/forsigtighed Medicinrådet har ikke fundet anledning til at inddrage forhold vedrørende alvorlighed eller forsigtighed i anbefalingen. Side 5 af 8

7 9 Sammensætning af fagudvalg og kontaktinformation til Medicinrådet Medicinrådets fagudvalg vedrørende psoriasis og psoriasis med ledgener Forvaltningslovens 4, stk. 2, har været anvendt i forbindelse med udpegning af medlemmer til dette fagudvalg. Formand Diljit Kaur Knudsen Speciallæge Medlemmer Trine Høgsberg Afdelingslæge Dermatologi ikke repræsenteret Sumangali Chandra Prasad Speciallæge Kan ikke udpege en kandidat, der opfylder Medicinrådets habilitetskrav Lone Skov Klinisk professor, overlæge, dr.med. Thomas Loof Hedegård Farmaceut Maija Bruun Haastrup Klinisk farmakolog Eli Glückstadt Patient/patientrepræsentant Andreas H.M. Jensen Patient/patientrepræsentant Indstillet af Lægevidenskabelige Selskaber Udpeget af Region Midtjylland Region Nordjylland Region Syddanmark Region Sjælland Region Hovedstaden Dansk Selskab for Sygehusapoteksledelse Dansk Selskab for Klinisk Farmakologi Danske Patienter Danske Patienter Tidligere medlemmer, som har taget del i processen: Lars Erik Bryld, overlæge, ph.d. og Lars Iversen, professor. Medicinrådets sekretariat Medicinrådet Dampfærgevej 27-29, 3. th København Ø medicinraadet@medicinraadet.dk Sekretariatets arbejdsgruppe: Jeppe Schultz Christensen (projekt- og metodeansvarlig) Mette Hollensted (projektdeltager) Madina Saidj (projektdeltager) Ilse Linde (fagudvalgskoordinator) Jan Odgaard-Jensen (biostatistiker) Bettina Fabricius Skov Christensen (informationsspecialist) Kirsten Holdt Henningsen (teamleder) Side 6 af 8

8 10 Versionslog Version Dato Ændring Godkendt af Medicinrådet. Side 7 af 8

9 11 Bilag Bilagsliste: Amgros beslutningsgrundlag Amgros sundhedsøkonomiske analyse Høringssvar fra ansøger Vurdering af den kliniske merværdi af tildrakizumab Ansøgers endelige ansøgning Protokol for vurdering af den kliniske merværdi af tildrakizumab Side 8 af 8

10 Amgros I/S Dampfærgevej København Ø Danmark T F Medicin@amgros.dk Beslutningsgrundlag til Medicinrådet Dette dokument er Amgros vurdering af tildrakizumab (Ilumetri) indiceret til behandling af moderat til svær plaque psoriasis hos voksne ( 18 år), som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisartropati (PsA). Vurderingen er baseret på lægemidlets gennemsnitlige inkrementelle omkostninger, baseret på SAIP (sygehusapotekets indkøbspris) sammenholdt med Medicinrådets vurdering af den kliniske merværdi. Dato for Medicinrådsbeslutning Firma Lægemiddel Almirall (ansøger) Tildrakizumab (Ilumetri) Indikation Behandling af moderat til svær plaque psoriasis hos voksne ( 18 år), som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisartropati. Amgros vurdering Amgros vurderer, at der ikke er et rimeligt forholdet mellem meromkostningerne og den kliniske merværdi for tildrakizumab (Ilumetri) som mulig standardbehandling til voksne ( 18 år) med moderat til svære plaque psoriasis, som er kandidater til 2. generations immun-modulerende behandling og ikke har psoriasisatropati. Herunder subpopulationen der omfatter patienter, som har haft behandlingssvigt på biologiske lægemidler generelt samt specifikt på lægemidler IL-23 og IL- 12/23 target. 1/5

11 Overordnet konklusion Medicinrådet har vurderet, at tildrakizumab (Ilumetri) sammenlignet med de mulige komparatorer giver ingen klinisk merværdi. Behandling med tildrakizumab (Ilumetri) er forbundet med meromkostninger sammenlignet med den billigste 1. linjebehandling til nævnte indikation. Amgros vurderer, at der ikke er rimeligt forhold mellem den kliniske merværdi for tildrakizumab (Ilumetri), sammenlignet med behandling med den billigste komparator i 1. linjebehandling. Meromkostninger drives af prisen på tildrakizumab (Ilumetri) og komparator. Behandling med tildrakizumab (Ilumetri) er forbundet med besparelser hvis der sammenlignes med flere andre komparatorer end den billigste til nævnte indikation. Andre overvejelser Amgros har indgået en aftale med Almirall om indkøb af tildrakizumab (Ilumetri) til en aftalepris, som er lavere end AIP. Amgros vurdering af tildrakizumab (Ilumetri) resulterer i både meromkostninger og besparelser afhængig af valgte komparator. Amgros vurderer forholdet til den kliniske merværdi sammenlignet med billigste mulige komparator (adalimumab) i behandlingslinjen. Tildrakizumab (Ilumetri) kan ifølge SPC et gives i dosis 200 mg til patienter der vejer 90 kg. Anvendes tildrakizumab (Ilumetri) i en dosis på 200 mg, er tildrakizumab (Ilumetri) forbundet med meromkostninger sammenlignet med behandling med alle komparatorer i 1. linjebehandlingen. I forhold til nuværende behandlingsvejledning er det Amgros vurdering, at det vil være hensigtsmæssigt, at tildrakizumab (Ilumetri) anbefales, så den i fremtiden kan konkurrenceudsættes på lige fod med øvrige 1. linjebehandlinger. Amgros har en kontrakt med Almirall indtil /5

12 Konklusion for populationen Tabel 1 Merværdi, meromkostninger og Amgros vurdering (baseret på SAIP) Population Komparator Merværdi Usikkerhed for klinisk merværdi Amgros konklusion om forholdet mellem meromkostninger og merværdi Voksne ( 18 år) med moderat til svære plaque psoriasis, som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisatropati. Herunder subpopulationen der omfatter patienter, som har haft behandlingssvigt ved anvendelse af en 1. linje IL-23 og IL-12/23 target. Adalimumab Ingen klinisk merværdi Lav evidenskvalitet Ikke rimeligt Supplerende informationer (resumé af resultaterne fra afrapporteringen) Konklusion på omkostnings- og budgetkonsekvensanalyserne Resultatet fra Amgros afrapportering på omkostningsanalyserne er gengivet i det følgende. For uddybende gennemgang af analyse og resultater henvises til afrapporteringen på Amgros afrapportering - Inkrementelle omkostninger per patient Behandling med tildrakizumab (Ilumetri) er forbundet med meromkostninger sammenlignet med behandling med billigste 1. linjebehandling til indikationen. I tabel 2 ses de inkrementelle omkostninger for tildrakizumab (Ilumetri) og komparatorerne. Amgros hovedanalyse resulterer i gennemsnitlige meromkostninger per patient for tildrakizumab (Ilumetri) sammenlignet med billigste komparator i 1. linjebehandling på ca. XXXXXXXDKK og ca. XXXXXXX DKK for lægemidlet med samme target (guselkumab) som tildrakizumab (Ilumetri). I tabellen ses alle inkrementelle omkostninger for tildrakizumab (Ilumetri) og komparatorerne i SAIP. 3/5

13 Tabel 2: 18 mdr. behandling sammenlignet med andre 1. linjebehandlinger, DKK, SAIP 18 måneder Lægemiddelomkostninger (SAIP) Inkrementelle omkostninger (SAIP) Tildrakizumab (Ilumetri) XXXXXX - Adalimumab (Imraldi) XXXXXX XXXXXX Certolizumab pegol (Cimzia) XXXXXXX XXXXXXXX Secukinumab (Cosentyx) XXXXXXX XXXXXXXX Ustekinumab (Stelara) XXXXXXX XXXXXXXX Guselkumab (Tremfya) XXXXXXX XXXXXXXX Ixekizumab (Taltz) XXXXXX XXXXXXX Brodalumab (Kyntheum) XXXXXXX XXXXXXXX Hvis analysen udføres på baggrund af AIP, bliver de inkrementelle omkostninger for tildrakizumab (Ilumetri) sammenlignet med den billigste komparator i 1. linjebehandling ca DKK. I tabel 3 ses de inkrementelle meromkostninger og lægemiddelomkostninger for alle komparatorer i AIP-priser. Tabel 3: 18 mdr. behandling sammenlignet med andre 1. linjebehandlinger, DKK, AIP 18 måneder Lægemiddelomkostninger (AIP) Inkrementelle omkostninger (AIP) Tildrakizumab (Ilumetri) Adalimumab (Imraldi) Certolizumab pegol (Cimzia) Secukinumab (Cosentyx) Ustekinumab (Stelara) Guselkumab (Tremfya) Ixekizumab (Taltz) Brodalumab (Kyntheum) /5

14 Amgros afrapportering Budgetkonsekvenser Amgros vurderer at anbefaling af tildrakizumab (Ilumetri) som mulig standardbehandling, vil resultere i budgetkonsekvenser på ca. XXXXXXXXX DKK per år. Udføres analysen i AIP er budgetkonsekvenserne på ca DKK, hvis tildrakizumab (Ilumetri) anbefales. Budgetkonsekvenser er beregnet ud fra et markedsperspektiv, og der ses derfor på hvilket lægemiddel tildrakizumab (Ilumetri) vil erstatte i gruppen for 1. linjebehandling til svær plaque psoriasis, og ikke hvilket lægemiddel i gruppen for 1. linjebehandling der er det billigste. Budgetkonsekvenserne kan være forbundet med større besparelser, da tildrakizumab (Ilumetri) er forbundet med besparelser sammenlignet med alle andre komparatorer end adalimumab i behandlingslinjen. Tildrakizumab (Ilumetri) vil derfor erstatte flere lægemidler inden for behandlingslinjen, for patienter der skifter behandling. Der er store usikkerheder forbundet med den potentielle besparelse ved anbefaling af tildrakizumab (Ilumetri). 5/5

15 TILDRAKIZUMAB (ILUMETRI) MODERAT TIL SVÆR PLAQUE PSORIASIS HOS VOKSNE AMGROS 26. marts 2019

16 OPSUMMERING Baggrund Tildrakizumab (Ilumetri) er en systemisk biologisk antistofbehandling indiceret til behandling af moderat til svær plaque psoriasis hos voksne, som er kandidater til 2. generations immunmodulerende behandling. Der forventes at ca. 100 nye patienter per år kandiderer til 2. generations immunmodulerende behandling, derudover forventes det, at ca. 100 patienter per år fejler på et 2. generations immunmodulerende lægemiddel og skal skifte til et andet. Amgros vurdering tager udgangspunkt i dokumentationen indsendt af Almirall. Analyse I analysen estimeres de inkrementelleomkostninger forbundet med behandling med tildrakizumab (Ilumetri) sammenlignet med behandling med guselkumab, adalimumab, secukinumab, ixekizumab, ustekinumab, brodalumab og certolizumab pegol til voksne ( 18 år), herunder subpopulationen af patienter med tidligere behandlingssvigt ved anvendelse af en 1. linje med IL-23 og IL-12/23 target. Inkrementelle omkostninger og budgetkonsekvenser Amgros har vurderet de gennemsnitlige inkrementelleomkostninger per patient ved brug af tildrakizumab (Ilumetri) sammenlignet med komparator. De inkrementelle omkostninger er angivet i SAIP. I analysen, som Amgros mener er mest sandsynlig, er de inkrementelle omkostninger for tildrakizumab (Ilumetri) ca. XXXXXX DKK sammenlignet med den billigste komparator i 1. linjebehandling til ca. XXXXXXXX DKK for den dyreste komparator i 1. linjebehandling for 18 måneder, for den generelle patientpopulation herunder subpopulationen af patienter med tidligere behandlingssvigt ved anvendelse af en 1. linje med IL-23 og IL-12/23 target. Anvendes lægemiddelpriserne i AIP er de inkrementelle omkostninger for tildrakizumab (Ilumetri) ca DKK sammenlignet med den billigste komparator i 1. linjebehandling til ca DKK for den dyreste komparator i 1. linjebehandling. Amgros vurderer at budgetkonsekvenserne for regionerne per år ved anbefaling af tildrakizumab (Ilumetri) som standardbehandling vil være ca. XXXXXXXXX DKK. Hvis analysen udføres med AIP, er budgetkonsekvenserne ca DKK om året. Konklusion Amgros kan konkludere, at behandling med tildrakizumab (Ilumetri) er forbundet med meromkostninger sammenlignet med den billigste komparator i 1. linjebehandling, men besparelser sammenlignet med andre komparatorer i 1. linjebehandling. Meromkostningerne eller besparelserne for tildrakizumab (Ilumetri) er i denne analyse udelukkende drevet af lægemiddelomkostninger for tildrakizumab (Ilumetri) og komparator. 2 TILDRAKIZUMAB (ILUMETRI)

17 Liste over forkortelser AIP DKK DRG IL mab PsA SPC Apotekernes indkøbspris Danske kroner Diagnose Relaterede Grupper Interleukin Monoklonalt antistof Psoriasisartropati Summary of Product Characteristics 3 TILDRAKIZUMAB (ILUMETRI)

18 INDHOLD Opsummering 2 Liste over forkortelser 3 1 Baggrund Problemstilling Patientpopulation Behandling med tildrakizumab (Ilumetri) Komparator Medicinrådets kliniske spørgsmål 7 2 Vurdering af indsendt økonomisk analyse Model, metode og forudsætninger Modelbeskrivelse Analyseperspektiv Omkostninger 8 3 Resultater Ansøgers hovedanalyse Antagelser i ansøgers hovedanalyse Resultat af ansøgers hovedanalyse Amgros hovedanalyse Antagelser i Amgros hovedanalyse Resultat af Amgros hovedanalyse 10 4 Budgetkonsekvenser 12 5 Diskussion 13 6 referencer 14 4 TILDRAKIZUMAB (ILUMETRI)

19 LOG Ansøgning Lægemiddelfirma: Handelsnavn: Generisk navn: Indikation: ATC-kode: Almirall Ilumetri Tildrakizumab Behandling af moderat til svær plaque psoriasis hos voksne ( 18 år), som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisartropati. L04AC17 Proces Ansøgning modtaget hos Amgros: Endelig rapport færdig: Sagsbehandlingstid fra endelig ansøgning: Arbejdsgruppe: 98 dage Louise Greve Dal Line Brøns Jensen Lianna Christensen Mark Friborg Pernille Winther Johansen Priser Denne rapport bygger på analyser udført på baggrund sygehusapotekernes indkøbspriser (SAIP). Enkelte steder er analysens resultat yderligere angivet på baggrund af listepriser (AIP). 5 TILDRAKIZUMAB (ILUMETRI)

20 1 BAGGRUND Tildrakizumab (Ilumetri) er som enkeltstofbehandling indiceret til behandling af moderat til svær plaque psoriasis hos voksne ( 18 år), som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisartropati(psa)(1). Almirall (herefter omtalt som ansøger) er markedsføringstilladelsesindehaver af tildrakizumab (Ilumetri) og har den indsendt en ansøgning til Medicinrådet om anbefaling af tildrakizumab (Ilumetri) som standardbehandling på danske sygehuse af den nævnte indikation. Som et led i denne ansøgning vurderer Amgros, på vegne af Medicinrådet de økonomiske analyser, ansøger har sendt som en del af den samlede ansøgning til Medicinrådet. Denne rapport er Amgros vurdering af de fremsendte økonomiske analyser (herefter omtalt som analysen). 1.1 Problemstilling Formålet med analysen er at estimere de inkrementelle omkostninger forbundet med behandling af moderat til svær plaque psoriasis hos voksne ( 18 år), som er kandidater til 2. generations immunmodulerende behandling og ikke har PsA, i form af de gennemsnitlige inkrementelle omkostninger per patient og de samlede budgetkonsekvenser for regionerne ved anbefaling af tildrakizumab (Ilumetri) som standardbehandling på danske sygehuse af den nævnte indikation. I analyserne sammenlignes behandling med tildrakizumab (Ilumetri) med behandling med guselkumab, adalimumab, secukinumab, ixekizumab, ustekinumab, brodalumab og certolizumab pegol, der er defineret i Medicinrådets protokol som nuværende standardbehandling(1). 1.2 Patientpopulation Psoriasis er en autoimmun, kronisk, inflammatorisk sygdom, hvor plaque psoriasis er den mest almindelige (ca. 80%). Det forventede antal patienter på landsplan er per år ca. 100 nye patienter, som er kandidater til 2. generations immunmodulerende behandling. Det drejer sig om psoriasispatienter, der opfylder kriterierne for biologisk behandling, og som ikke har psoriasisartropati (PsA). Derudover forventes det, at ca. 100 patienter per år fejler på et 2. generations immunmodulerende lægemiddel og skal skifte til et andet lægemiddel(1). Adalimumab, secukinumab, ixekizumab og ustekinumab anbefales aktuelt alle som 1. linjebehandlinger til psoriasis begrundet i samme effekt på hudsymptomer og sammenlignelig bivirkningsprofil(1). Lægemidlerne brodalumab og guselkumab er af Medicinrådet (15. marts 2018) vurderet til at gøre et klinisk ligestillet alternativ 1. linjebehandling(2,3). Lægemidlet certolizumab pegol er af medicinrådet (12. december 2018) vurderet til at gøre et klinisk ligestillet alternativ til 1. linjebehandling(4).xx 1.3 Behandling med tildrakizumab (Ilumetri) Indikation Tildrakizumab (Ilumetri) er indiceret til behandling af Voksne ( 18 år) med moderat til svær plaque psoriasis, som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisartropati. Herunder subpopulationen der omfatter patienter, som har haft behandlingssvigt på biologiske lægemidler generelt samt specifikt på lægemidler med IL-23 og IL-12/23 target(1). Virkningsmekanisme Tildrakizumab (Ilumetri) er et humant monoklonalt antistof (mab), som binder selektivt til interleukin (IL)-23(1). Dosering Enkeltstofbehandlingen administreres således(1): Tildrakizumab (Ilumetri), subkutan injektion á 100 mg i uge 0, 4 og herefter hver 12. uge Komparator 6 TILDRAKIZUMAB (ILUMETRI)

21 Medicinrådet har defineret komparator som de lægemidler, der aktuelt anbefales som 1. linjebehandling, til den generelle patientpopulation med moderat til svær plaque psorasis. Heraf er ustekinumab og guselkumab henholdsvis et anti-interleukin(il)-12/23 og anti-il-23, der derfor deler samme target som tildrakizumab (Ilumetri)(1). Tabel 1: Definerede populationer og komparatorer Population Komparator Voksne ( 18 år) med moderat til svær plaque psoriasis, som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisartropati. (Herunder subpopulation som har haft behandlingssvigt ved anvendelse af en 1. linje IL-23 og IL-12/23 targit) Adalimumab Secukinumab Ixekizumab Ustekinumab Brodalumab Guselkumab Certolizumab pegol 1.4 Medicinrådets kliniske spørgsmål Medicinrådet har vurderet den kliniske merværdi af behandling med tildrakizumab (Ilumetri) sammenlignet med komparator for voksne ( 18 år) med moderat til svær plaque psoriasis, som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisartropati(1). 7 TILDRAKIZUMAB (ILUMETRI)

22 2 VURDERING AF INDSENDT ØKONOMISK ANALYSE I analysen af gennemsnitlige behandlingsomkostninger per patient sammenlignes behandling med tildrakizumab (Ilumetri) med behandling med guselkumab (Tremfya) til voksne ( 18 år) med moderat til svær plaque psoriasis uden PsA, som er kandidater til 2. generations immunmodulerende behandling, herunder subpopulationen af patienter med tidligere behandlingssvigt ved anvendelse af en 1. linje IL-23 og IL-12/23 target. 2.1 Model, metode og forudsætninger Modelbeskrivelse Ansøger har indsendt en simpel omkostningsmodel for behandling af patienter i den nævnte population. Ansøger antager at behandlingsforløbene for tildrakizumab (Ilumetri) og guselkumab (Tremfya) er identiske og at effekt- og bivirkningsprofil er helt ens. Frafald inkluderes således ikke i analysen I modellen antages, at der behandles i 18 måneder. Behandling vil have færre omkostninger efterfølgende år. Ansøger har ikke indsendt nogen følsomhedsanalyser. Amgros vurdering Amgros accepterer ansøgers antagelser om ens patientforløb for tildrakizumab (Ilumetri) og guselkumab (Tremfya), da der ikke er forskelle i udredning, diagnostik, behandlingsmåde eller opfølgning mellem tildrakizumab (Ilumetri) og komparator. Udfaldet efter 12 måneder er at forsætte i behandling eller at seponere behandling. Amgros mener at ansøgers hovedanalyse på 18 måneder inkluderer alle relevante omkostninger for behandlingerne. Der er i Medicinrådets protokol defineret flere mulige komparatorer til tildrakizumab (Ilumetri) for populationen(1). Amgros mener derfor, at det i hovedanalysen er relevant at estimere de inkrementelle omkostninger for alle mulige komparatorer jf. tabel. Amgros udarbejder i sin hovedanalyse behandlingssammenligning med tildrakizumab (Ilumetri) med komparativerne defineret i protokollen. Amgros vurderer, at det er rimeligt ikke at inkludere frafald i modellen, da der ikke findes data der understøtter, at der vil være forskel i frafaldsraten mellem de sammenlignende lægemidler. Amgros udarbejder en ny hovedanalyse hvor de inkrementelle omkostninger for tildrakizumab (Ilumetri) sammenlignet med alle relevante komparatorer hvor omkostninger estimeres for 18 måneder Analyseperspektiv Analysen inkluderer udelukkende lægemiddelomkostninger. Tidshorisonten i analysen er fra første dosis og 18 måneder frem. Ansøger har diskonteret omkostninger efter 12 måneder med en diskonteringsfaktor på 4%. Amgros vurdering Analysens perspektiv er i tråd med Amgros retningslinjer, Jf. Amgros Metodevejledning om, hvad der må inkluderes i en økonomisk analyse. Amgros vurderer, at tidshorisonten er tilstrækkeligt lang til at opfange betydelige relevante forskelle mellem de sammenlignede interventioner i analysen for den angivne population, da patienterne får behandling i 12 måneder eller potentielt får behandling i mange år, og hvor antallet af administrationer differentiere fra år 1 og efterfølgende år, hvormed det er relevant at estimere omkostninger for 12 måneder og derefter for efterfølgende måneder. Amgros godtager analysens perspektiv og tidshorisonten Omkostninger 8 TILDRAKIZUMAB (ILUMETRI)

23 Lægemiddelomkostninger Ansøger har for tildrakizumab (Ilumetri) og guselkumab (Tremfya) anvendt SPC erne for lægemidlerne(5,6). Alle anvendte lægemiddelpriser er i SAIP. Tabel 2 illustrerer de lægemiddelpriser, som anvendes i analysen. Tabel 2: Anvendte lægemiddelpriser, SAIP (april 2019) Lægemiddel Styrke Pakningsstørrelse Pris pr pakning (DKK) Kilde Tildrakizumab (Ilumetri) Guselkumab (Tremfya) 100 mg, s.c 1 stk. XXXXXXXXX Ansøger 100 mg, s.c 1 stk. XXXXXXXXX Amgros Tildrakizumab (Ilumetri) administreres med 100 mg i uge 0, 4 og derefter hver 12. uge, tilsvarende 5 administrationer over år 1 og 7,17 over 18 måneder. Guselkumab (Tremfya) administreres med 100 mg i uge 0, 4 og derefter hver 8. uge, tilsvarende 7 administrationer i år 1 og 10,25 administrationer over 18 måneder. Tabel 3 illustrerer doseringen af lægemidlerne, som anvendes i analysen og prisen per patient for hver population. Tabel 3: Gennemsnitlig dosis og lægemiddelomkostninger pr. patient over 18 måneder, DKK Behandlingsregime Styrke Administrationer Pris pr. enhed I alt 18 måneder Tildrakizumab (Ilumetri) 100 mg, s,c 7,17 XXXXXXXXX XXXXXXXXXX Guselkumab (Tremfya) 100 mg, s.c 10,25 XXXXXXXXX XXXXXXXXXX Amgros vurdering Doseringen af lægemidlerne er i tråd med lægemidlernes SPC er(5,6). Amgros accepterer den valgte dosering. 9 TILDRAKIZUMAB (ILUMETRI)

24 3 RESULTATER 3.1 Ansøgers hovedanalyse Antagelser i ansøgers hovedanalyse Tidshorisonten er 18 måneder i analysen for tildrakizumab (Ilumetri) og guselkumab (Tremfya) Der inkluderes udelukkende lægemiddelomkostninger i analysen Det antages, at subpopulationen med patienter, som har haft behandlingssvigt ved anvendelse af en 1. linje med IL-23 eller IL-12/23 target, også dækkes af hovedpopulationen Resultat af ansøgers hovedanalyse Resultaterne fra ansøgers hovedanalyse præsenteres i tabel 4. Tabel 4: Resultat af ansøgers hovedanalyse, gns. omkostninger per patient, 18 måneder, DKK, SAIP Tildrakizumab (Ilumetri) Guselkumab (Tremfya) Inkrementelle omkostninger (DKK) XXXXXXXXX DKK XXXXXXXXXX DKK XXXXXXX 3.2 Amgros hovedanalyse Antagelser i Amgros hovedanalyse Amgros inkluderer alle relevante komparatorer i analysen Resultat af Amgros hovedanalyse Resultaterne fra Amgros hovedanalyse præsenteres nedenfor. 10 TILDRAKIZUMAB (ILUMETRI)

25 Tabel 5: Anvendte lægemiddelpriser, SAIP (april 2019) Lægemiddel Styrke Pakningsstørrelse Pris pr pakning (DKK) Kilde Tildrakizumab (Ilumetri) 100 mg, s.c 1 stk. XXXXXXXXX Ansøger Guselkumab (Tremfya) 100 mg, s.c 1 stk. XXXXXXXXX Amgros Adalimumab (Imraldi) 40 mg, s.c 2 stk. XXXXXXXX Amgros Secukinumab (Cosentyx) 300 mg, s.c 2 stk. XXXXXXXX Amgros Ustekinumab (Stelara) 100 kg: 45 mg, s.c >100 kg: 90 mg, s.c 1 stk. XXXXXXXXX Amgros Certolizumab pegol 200 mg, s.c 1 stk. XXXXXXX Amgros Ixekizumab (Taltz) 80 mg, s.c 1 stk XXXXXXXX Amgros Brodalumab (Kyntheum) 210 mg, s.c 2 stk. XXXXXXXX Amgros I tabel 6 ses resultatet af Amgros hovedanalyse. Tabel 6: 18 mdr. behandling sammenlignet med andre 1. linjebehandlinger, DKK, SAIP 18 måneder Lægemiddelomkostninger (SAIP) Inkrementelleomkostninger (SAIP) Tildrakizumab (Ilumetri) XXXXXX - Adalimumab (Imraldi) XXXXXX XXXXXX Certolizumab pegol (Cimzia) XXXXXXX XXXXXXXX Secukinumab (Cosentyx) XXXXXXX XXXXXXXX Ustekinumab (Stelara) XXXXXXX XXXXXXXX Guselkumab (Tremfya) XXXXXXX XXXXXXXX Ixekizumab (Taltz) XXXXXX XXXXXXX Brodalumab (Kyntheum) XXXXXXX XXXXXXXX De inkrementelle omkostninger for tildrakizumab (Ilumetri) er ca. XXXXXXXX DKK per patient for lægemidler med target IL-23 (guselkumab). De inkrementelle omkostninger for tildrakizumab (Ilumetri) sammenlignet med behandling med billigste komparator i 1. linjebehandling (adalimumab) er på ca. XXXXXX DKK. Hvis analysen udføres med AIP, er de inkrementelle omkostninger for tildrakizumab (Ilumetri) sammenlignet med guselkumab ca DKK og ca DKK sammenlignet med behandling med billigste komparator i 1. linjebehandling (adalimumab). 11 TILDRAKIZUMAB (ILUMETRI)

26 4 BUDGETKONSEKVENSER Anbefaling af tildrakizumab (Ilumetri) som standardbehandling til indikationen omhandlet af denne analyse, vil ikke udvide brugen af immunsupprimerende lægemidler til behandling af moderat til svær plaque psoriasis hos voksne ( 18 år), som er kandidater til 2. generations immunmodulerende behandling, men i stedet øge konkurrencen om det eksisterende marked. Ansøger antager at tildrakizumab (Ilumetri) kun vil blive anvendt til skiftepatienter hvis tildrakizumab (Ilumetri) anbefales. Dette betyder at 0% vil blive behandlet med tildrakizumab (Ilumetri) for bionaïve patienter. Ansøger antager at 27% af de 100 skifte-patienter vil blive behandlet med tildrakizumab (Ilumetri) såfremt tildrakizumab (Ilumetri) anbefales. Ansøger antager at skifte-patienterne der behandles såfremt tildrakizumab (Ilumetri) anbefales erstatter lægemidlet guselkumab (Tremfya) der har samme target som tildrakizumab (Ilumetri). Med de nuværende priser på lægemidlerne vil tildrakizumab (Ilumetri) således være resulterende i budgetkonsekvenser på ca. XXXXXXXXX DKK per budget år. Amgros mener tildrakizumab (Ilumetri) vil anvendes til flere af de 100 skifte-patienter, og dermed også tage markedsandele fra andre komparatorer end guselkumab (Tremfya). Amgros mener derfor at budgetkonsekvenserne fører til en større besparelse af budgetkonsekvenserne end ansøgers estimat. Den potentielle besparelse kendes ikke. Angives lægemidlerne i AIP vil budgetkonsekvenserne resultere i ca DKK per budget år. 12 TILDRAKIZUMAB (ILUMETRI)

27 5 DISKUSSION Ansøger har kun inkluderet lægemiddelomkostninger, eftersom det er accepteret, at behandlingerne er ligeværdige med hensyn til effekt og bivirkningsprofil. Alle lægemidler administreres subkutant, og derfor antages ens administrationsomkostninger. Der vil dog være forskel i antal doser år 1 og efterfølgende år. Amgros vurderer, at de inkrementelle omkostninger med behandling med tildrakizumab (Ilumetri) er ca. XXXXXX DKK for 18 måneder sammenlignet med den billigste komparator i 1. linjebehandling. Amgros vurderer, at anbefalingen af tildrakizumab (Ilumetri) vil resultere i budgetkonsekvenser på ca. XXXXXXXXXX DKK per budget år.budgetkonsekvenserne er beregnet på hvilket lægemiddel tildrakizumab (Ilumetri) vil erstatte i gruppen for 1. linjebehandling til svær plaque psoriasis. Da tildrakizumab (Ilumetri) forventes at tage markedsandel fra flere dyrere alternativer, vil budgetkonsekvenserne være yderligere forbundet med besparelser Angives lægemidlerne i AIP, vil de inkrementelle omkostninger med behandling med tildrakizumab (Ilumetri) være ca DKK for 18 måneder sammenlignet med billigste komparator i 1. linjebehandling (adalimumab) og budgetkonsekvenser på ca DKK per budget år. 13 TILDRAKIZUMAB (ILUMETRI)

28 6 REFERENCER 1. Medicinrådet. Medicinrådets protokol for vurdering af klinisk merværdi for tildrakizumab til behandling af moderat til svær plaque psoriasis. : Medicinrådet. Medicinrådets anbefaling vedrørende guselkumab til moderat til svær plaque psoriasis [Internet] p Available from: 3. Medicinrådet. Medicinrådets anbefaling vedrørende brodalumab til moderat til svær plaque psoriasis [Internet] p Available from: 4. Medicinrådet. Baggrund for Medicinrådets anbefaling vedrørende certolizumab pegol som mulig standardbehandling til moderat til svær plaque psoriasis. 2018;(december). Available from: 5. EMA - European Medicines Agency. SUMMARY OF PRODUCT CHARACTERISTICS - IIUMETRI. 6. EMA - European Medicines Agency. SUMMARY OF PRODUCT CHARACTERISTICS - TREMFYA. 14 TILDRAKIZUMAB (ILUMETRI)

29 REGIONERNES LÆGEMIDDELORGANISATION AMGROS I/S DAMPFÆRGEVEJ KØBENHAVN Ø TLF:

30

31 Medicinrådets vurdering af klinisk merværdi for tildrakizumab til behandling af moderat til svær plaque psoriasis Versionsnr. 1.0

32 Om Medicinrådet Medicinrådet er et uafhængigt råd, som udarbejder anbefalinger og vejledninger om lægemidler til de fem regioner. Medicinrådet vurderer, om nye lægemidler og nye indikationer kan anbefales som standardbehandling og udarbejder fælles regionale behandlingsvejledninger. Nye lægemidler vurderes i forhold til effekt, eksisterende behandling og pris. Det skal give lavere priser og lægemidler, der er til størst mulig gavn for patienterne. De fælles regionale behandlingsvejledninger er vurderinger af, hvilke lægemidler der er mest hensigtsmæssige til behandling af patienter inden for et terapiområde og dermed grundlag for ensartet høj kvalitet for patienterne på tværs af sygehuse og regioner. Om vurderingen af klinisk merværdi Vurderingen af klinisk merværdi er Medicinrådets vurdering af, hvor effektiv og sikkert lægemidlet er i forhold til andre lægemidler til den samme gruppe patienter. Vurderingen af klinisk merværdi indgår, når Medicinrådet skal beslutte, om lægemidlet anbefales som mulig standardbehandling. Se Medicinrådets metodehåndbog for yderligere information. Dokumentoplysninger Godkendelsesdato Ikrafttrædelsesdato Dokumentnummer Versionsnummer 13. marts marts Medicinrådet, Publikationen kan frit refereres med tydelig kildeangivelse. Medicinrådet, Dampfærgevej 27-29, 3. th., 2100 København Ø Sprog: dansk Format: pdf Udgivet af Medicinrådet, 13. marts 2019 Side 1 af 33

33 Indhold 1 Lægemiddelinformationer Medicinrådets konklusion vedrørende klinisk merværdi Forkortelser Formål Baggrund Metode Litteratursøgning Databehandling Klinisk merværdi... 9 Konklusion klinisk spørgsmål Gennemgang af studier Resultater og vurdering Evidensens kvalitet Konklusion for voksne ( 18 år) med moderat til svær plaque psoriasis Andre overvejelser Fagudvalgets vurdering af samlet klinisk merværdi og samlet evidensniveau Rådets vurdering af samlet klinisk merværdi og samlet evidensniveau Relation til eksisterende behandlingsvejledning Referencer Sammensætning af fagudvalg og kontaktinformation til Medicinrådet Versionslog Bilag 1: GRADE-evidensprofiler Cochrane Risk of Bias resurface resurface VOYAGE VOYAGE GRADE-evaluering af evidenskvaliteten til vurdering af den kliniske merværdi af tildrakizumab GRADE evidensprofil, tildrakizumab vs. placebo GRADE evidensprofil, guselkumab vs. placebo Side 2 af 33

34 1 Lægemiddelinformationer Lægemidlets oplysninger Handelsnavn Generisk navn Firma ATC-kode Virkningsmekanisme Administration/dosis EMA-indikation Ilumetri tildrakizumab Almirall L04AC17 Humaniseret monoklonalt antistof rettet mod interleukin (IL)-23. Subkutan injektion 100 mg i uge 0, 4 og hver 12. uge herefter. Behandling af moderat til svær plaque psoriasis hos voksne ( 18 år), som er kandidater til systemisk behandling. 2 Medicinrådets konklusion vedrørende klinisk merværdi Medicinrådet vurderer, at tildrakizumab til voksne ( 18 år) patienter med moderat til svær plaque psoriasis, som er kandidater til 2. generations immunmodulerende behandling (behandling med biologiske lægemidler) og ikke har psoriasisartropati giver: Ingen klinisk merværdi til patienter med moderat til svær plaque psoriasis sammenlignet med guselkumab. Evidensens kvalitet vurderes at være lav. Den kliniske merværdi kan ikke vurderes for subpopulationen af patienter med tidligere behandlingssvigt på biologiske lægemidler generelt. Den kliniske merværdi kan ikke vurderes for subpopulationen af patienter med tidligere behandlingssvigt på biologiske lægemidler med samme target. Side 3 af 33

35 Medicinrådet kategoriserer lægemidlers kliniske merværdi i en af følgende kategorier: Kategori 1. Stor merværdi: Vedvarende og stor forbedring i effektforhold der ikke tidligere er opnået med et relevant behandlingsalternativ. Eksempler herpå er sygdomsremission, markant stigning i overlevelsestid, langvarigt fravær af alvorlige sygdomssymptomer eller udtalt fravær af alvorlige bivirkninger. Kategori 2. Vigtig merværdi: Markant forbedring, eksempelvis lindring af sygdomstilstand, moderat stigning i overlevelsestid, lindring af alvorlige symptomer, fravær af alvorlige bivirkninger og væsentligt fravær af andre bivirkninger. Kategori 3. Lille merværdi: Moderat forbedring, f.eks. reduktion i ikkealvorlige sygdomssymptomer eller fravær af bivirkninger. Kategori 4. Ingen merværdi: Ingen merværdi sammenlignet med standardbehandling/andre behandlinger. Kategori 5. Negativ merværdi: Negativ merværdi sammenlignet med standardbehandling/andre behandlinger. Kategori 6. Ikkedokumenterbar merværdi: Ikkedokumenterbar merværdi sammenlignet med standardbehandling/ andre behandlinger. Effektforskellen kan ikke kvantificeres ud fra det videnskabelige datagrundlag. Side 4 af 33

36 3 Forkortelser BSA: Body Surface Area CI: DDS: Dermbio: DLQI: EMA: GRADE: HR: IL: mab: OR: PASI: PGA: RR: SAE: TNF: Konfidensinterval Dansk Dermatologisk Selskab National database for psoriasispatienter i biologisk behandling Dermatology life quality index European Medicines Agency System til vurdering af evidens (Grading of Recommendations Assessment, Development and Evaluation) Hazard ratio Interleukin Monoklonalt antistof Odds ratio Psoriasis area and severity index Physician s Global Assessment Relativ risiko Alvorlig uønsket hændelse (serious adverse effect) Tumor necrosis factor Side 5 af 33

37 4 Formål Formålet med Medicinrådets vurdering af klinisk merværdi af tildrakizumab til moderat til svær plaque psoriasis er at vurdere den kliniske merværdi i forhold til et eller flere lægemidler til samme patientgruppe (komparator(er)). Den kliniske merværdi af tildrakizumab vurderes i den generelle population af voksne ( 18 år) med moderat til svær plaque psoriasis uden ledgener (psoriasisartropati), som er kandidater til 2. generations immunmodulerende behandling. Derudover vurderes den kliniske merværdi i subpopulationerne af patienter, som har haft behandlingssvigt på biologiske lægemidler generelt samt specifikt på lægemidler med IL-23 og IL-12/23 target. Med udgangspunkt i den kliniske merværdi og en omkostningsanalyse udarbejdet af Amgros vurderer Medicinrådet, om tildrakizumab anbefales som mulig standardbehandling. 5 Baggrund Moderat til svær plaque psoriasis I Danmark, som i øvrige dele af verden, får ca. 2-3 % af befolkningen psoriasis i løbet af livet. Psoriasis er en autoimmun, kronisk, inflammatorisk sygdom, hvor plaque psoriasis, også kaldet psoriasis vulgaris, er den mest almindelige (ca. 80 %) [1,2]. Der findes ikke et definitivt mål for sværhedsgraden af psoriasis. Dog anses sygdommen som moderat til svær, hvis enten psoriasis area and severity index (PASI) er over 10, eller det påvirkede overfladeareal (body surface area, BSA) er over 10, eller hvis patientens vurdering af livskvalitet, sædvanligvis vurderet ved dermatology life quality index (DLQI), er over 10. Samlet betegnes dette 10-reglen [3,4]. Bedømt på Dermbios seneste årsrapport fra 2017 er antallet af patienter, der er i biologisk behandling i Danmark, fortsat stigende. Ved udgangen af 2017 var der registreret 2710 patienter, der havde modtaget behandling med 2. generations immunmodulerende lægemidler [5]. Det forventede antal patienter på landsplan er pr. år ca. 100 nye patienter, som er kandidater til 2. generations immunmodulerende behandling. Det drejer sig om psoriasispatienter, der opfylder kriterierne for biologisk behandling, og som ikke har ledgener. Derudover forventes det, at ca. 100 patienter pr. år fejler på et 2. generations immunmodulerende lægemiddel og skal skifte til et andet lægemiddel [6]. I 2014 blev psoriasis anerkendt af World Health Organisation (WHO) som en alvorlig kronisk sygdom, der ofte er yderst smertefuld og invaliderende. Dette skyldes blandt andet den stigmatisering, som ofte er forbundet med sygdommen [7]. Livskvalitetsundersøgelser viser, at mænd og kvinder er ligeligt påvirket af psoriasis og at psoriasis kan påvirke patienten på linje med diabetes og hjertekarsygdomme [7]. Nuværende behandling 2. generations immunmodulerende behandling igangsættes efter kriterier defineret i RADSbehandlingsvejledningen [6] og retningslinjer fra Dansk Dermatologisk Selskab [8]. Disse omfatter bl.a., at patienten skal have psoriasis med svære hudmanifestationer, defineret som PASI 10, BSA 10 % eller DLQI 10. Side 6 af 33

38 Til behandling af moderat til svær psoriasis anvendes ti biologiske lægemidler med forskellige virkningsmekanismer: fire Tumor Nekrose Faktor-alfa (TNF-alfa) hæmmere (infliximab, certolizumab pegol, eternacept og adalimumab), et anti-interleukin (IL)-12/23 (ustekinumab), to anti-il-17 (secukinumab og ixekizumab), et anti-il-17ra (brodalumab), et anti-il-23 (guselkumab) og en PDE4-inhibitor (apremilast). De fleste af disse behandlinger virker dæmpende på immunsystemet. Adalimumab, certolizumab pegol, secukinumab, ixekizumab, brodalumab, guselkumab og ustekinumab anbefales alle som 1. linjebehandlinger til psoriasis, da de er vurderet til at have sammenlignelige effekter på hudsymptomer og sammenlignelige bivirkningsprofiler [9]. Patienterne vurderes før opstart, efter 12 ugers behandling og derefter mindst to gange årligt. Der er i DDSguidelines samt RADS vejledning opstillet kriterier for den forventede effekt på PASI, og hvornår behandlingsskift er nødvendigt. Alle patienter med psoriasis, som sættes i 2. generations immunmodulerende behandling, skal registreres i Dermbio-databasen. For patienter med moderat til svær psoriasis har de biologiske præparater medført en betydelig bedring i behandlingsrespons. Anvendelse af det nye lægemiddel Ilumetri er en systemisk, biologisk antistofbehandling, som administreres som injektion (subkutan á 100 mg i uge 0, 4 og herefter hver 12. uge). Indholdsstoffet tildrakizumab er et monoklonalt humaniseret antistof (mab), der specifikt binder sig til det ekstracellulære humane interleukin (IL)-23. Herved forhindres, at IL- 23 bidrager til immunaktivering, og samtidig begrænses den inflammatoriske reaktion i huden, der spiller en central rolle i udviklingen af psoriasis. Ilumetri har ikke indikation til patienter med ledgener. Hos patienter med specifikke karakteristika (bl.a. høj sygdomsbyrde, kropsvægt 90 kg) kan dosering med 200 mg overvejes [10]. 6 Metode De præspecificerede metoder i protokollen er udarbejdet af Medicinrådet. Ansøgningen er valideret af Medicinrådet. Ansøger har anvendt og fulgt den præspecificerede metode, jf. Medicinrådets protokol for vurdering af klinisk merværdi for tildrakizumab til behandling af moderat til svær plaque psoriasis - 1.0, som blev godkendt i Medicinrådet den 22.oktober Ansøger har valgt guselkumab som komparator og har udarbejdet en indirekte sammenligning med placebo som fælles komparator. De indirekte sammenlignende analyser (udarbejdet efter Buchers metode) er gennemført for effektmålene PASI 75, PASI 90, alvorlige uønskede hændelser (SAEs), DLQI og behandlingsophør, alle ved uge og Fagudvalget har anført i protokollen, at den samlede kliniske merværdi af tildrakizumab baseres på en tidshorisont på 1 år, og at der ønskes data med længst mulig opfølgningstid. Ansøger er derfor blevet bedt om at supplere uge og analyser med narrative sammenligninger af data for tildrakizumab og guselkumab af alle effektmål ved 1-års behandling. Tidshorisonten på 1 år er valgt som tidsenhed for alle effektmål for at kunne vurdere langtidseffekten og derved vedligeholdelsen af den kliniske effekt. Ansøger har tilkendegivet, at der ikke foreligger publicerede data for subpopulationerne, som omfatter patienter, der enten har haft behandlingssvigt ved anvendelse af et biologisk lægemiddel generelt eller ved et lægemiddel med samme target. Side 7 af 33

39 Ansøger har desuden belyst forhold vedr. mulighed for behandlingspause, dosisreduktion/behandlingsintervalforlængelse, herunder muligheden for behandling med 200 mg, forhold mellem initialdosis og vedligeholdelsesdosis samt vedligeholdelse af effekt mellem doseringer hver 12. uge, som efterspurgt af fagudvalget i protokollen. Fra evidens til kategori. Medicinrådet vurderer den kliniske merværdi af et lægemiddel ud fra den indsendte endelige ansøgning, evt. suppleret med andet materiale. I protokollen blev effektmålene angivet som kritiske, vigtige og mindre vigtige. I vurderingen af klinisk merværdi vægter de kritiske højest, de vigtige næsthøjest, og de mindre vigtige indgår ikke. Den kliniske merværdi kategoriseres først enkeltvis pr. effektmål, hvorefter der foretages en vurdering af den samlede kategori for lægemidlet på tværs af effektmålene. Kategoriseringen pr. effektmål foretages på baggrund af absolutte og relative værdier for det enkelte effektmål. Den relative effekt beskrives med et estimat og et konfidensinterval, der sammenholdes med generiske væsentlighedskriterier. Den absolutte effekt sammenholdes med den i protokollen beskrevne mindste klinisk relevante forskel. Den endelige kategorisering af lægemidlets kliniske merværdi er en delvis kvalitativ proces, hvor der foretages en vurdering af det samlede datagrundlag på tværs af effektmålene. Vurdering af evidensens kvalitet foretages med udgangspunkt i GRADE og udtrykker tiltroen til evidensgrundlaget for de enkelte effektstørrelser og den endelige kategori for klinisk merværdi. Evidensens kvalitet inddeles i fire niveauer: høj, moderat, lav og meget lav. GRADE-metoden er et internationalt anerkendt redskab til systematisk vurdering af evidens og udarbejdelse af anbefalinger. I denne vurdering er metoden anvendt til at vurdere evidensens kvalitet. 7 Litteratursøgning Ansøger har gennemført en systematisk litteratursøgning for det kliniske spørgsmål, som beskrevet i protokollen, og ansøgers litteratursøgning har resulteret i inklusion af nedenstående hovedstudier: resurface 1 og 2 publiceret af Reich et al., 2017 (tildrakizumab) [11]. VOYAGE 1 publiceret af Blauvelt et al., 2017 (guselkumab) [12]. VOYAGE 2 publiceret af Reich et al., 2017 (guselkumab) [13]. Othsuki et al., 2018 (guselkumab) [14]. Medicinrådet har, udover ovenstående studier, inddraget studieregistreringerne på clinicaltrials.gov, produktresuméer samt data i EPAR for både tildrakizumab og guselkumab. 8 Databehandling Ansøger har præsenteret sammenlignende analyser mellem tildrakizumab og komparator ved uge og på alle effektmål, hvor det var muligt. For tildrakizumab er uge 12-data for placebobehandlingen i resurface-studierne fremskrevet til uge 28, mens uge 16-data for placebobehandlingen i VOYAGEstudierne er fremskrevet til uge 24. Denne fremskrivning er foretaget, da fagudvalget ønsker længst mulig opfølgningstid og samtidig vurderer, at der fra uge 12 til 28 ikke sker en ændring i respons for placeboarmen ift. de præspecificerede effektmål. Fagudvalget vurderer endvidere, at data for uge 24 og 28 er sammenligneligt, og vurderingen af det kliniske spørgsmål vil derfor blive baseret på data for uge De forhåndsdefinerede mindste klinisk relevante forskelle til grundlag for vurderingen var, jf. protokollen, baseret på behandlingseffekter ved 1 år og ikke ved uge eller For tildrakizumab findes der kun Side 8 af 33

40 publicerede studier, som rapporterer data frem til uge 28 (resurface 1 og 2), mens der for guselkumab er publiceret data frem til uge 48 (VOYAGE 1 og 2). Ansøger har indsendt upublicerede data til besvarelse af det kliniske spørgsmål ved ~1 år, så disse er ikke indgået i fagudvalgets vurdering af tildrakizumab. På denne baggrund vurderer fagudvalget, at det tilgængelige datagrundlag ikke tillader vurdering af langtidseffekten af tildrakizumab. Medicinrådet har ikke fundet anledning til at foretage ændringer af beregninger foretaget af ansøger eller supplere med yderligere beregninger. 9 Klinisk merværdi Konklusion klinisk spørgsmål Hvad er den kliniske merværdi af tildrakizumab til voksne patienter med moderat til svær plaque psoriasis, som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisartropati? Fagudvalget vurderer, at tildrakizumab til patienter med moderat til svær plaque psoriasis giver ingen klinisk merværdi sammenlignet med guselkumab. Evidensens kvalitet er lav. Fagudvalget vurderer, at den kliniske merværdi af tildrakizumab ikke kan vurderes til subpopulationen af patienter med tidligere behandlingssvigt på biologiske lægemidler generelt. Fagudvalget vurderer, at den kliniske merværdi af tildrakizumab ikke kan vurderes til subpopulationen af patienter med tidligere behandlingssvigt på biologiske lægemidler med samme target Gennemgang af studier Karakteristika resurface 1 og resurface 2 (tildrakizumab) [11] resurface 1 og resurface 2 er to randomiserede, multicenter, dobbelt-blindede, kontrollerede fase 3- studier. I resurface 1 blev patienter (n = 772) randomiseret 2:2:1 til subkutan behandling med enten tildrakizumab 200 mg, tildrakizumab 100 mg eller placebo ved uge 0 og 4 (del 1). I resurface 2 blev patienter (n = 1090) randomiseret 2:2:1:2 til behandling med tildrakizumab 200 mg, tildrakizumab 100 mg, placebo eller etanercept. Ved afslutning af del 1 i både resurface 1 og 2 (dvs. ved uge 12) blev patienter, som frem til uge 12 havde modtaget placebo-behandling, re-randomiseret til at modtage enten tildrakizumab 200 mg eller 100 mg ved uge 12 og 16 og hver 12. uge derefter. I begge studier blev patienter, som ved uge 28 havde opnået PASI 50, re-randomiseret til behandling med enten tildrakizumab 100 mg, tildrakizumab 200 mg eller placebo. Patienter, som ved uge 28 ikke havde responderet på tildrakizumab (< PASI 50), blev ekskluderet. Behandlingen fortsatte derefter frem til hhv. uge 64 (resurface 1) og uge 52 (resurface 2). Re-randomisering ved uge 12 og 28 blev udført ift. region og stratificeret ift. kropsvægt ( 90 kg eller > 90 kg). Bivirkningsprofilen blev vurderet blandt alle randomiserede patienter, som enten i del 1 eller 2, og modtog mindst én dosis tildrakizumab. De primære endepunkter var andelen af patienter, som ved uge 12 havde opnået PASI 75 eller PGA-score på clear eller minimal med minimum en to-punkts reduktion fra baseline. Sekundære endepunkter inkluderede andelen af patienter, som havde opnået PASI 90 eller PASI 100 (uge 12), PASI 75 (uge 28), Side 9 af 33

41 DLQI-score på 0 eller 1 (uge 12 og 28) samt PGA-respons (uge 28). De primære endepunkter (PASI 75, PGA 0/1 samt sikkerhedsprofilen ved uge 12) og de vigtigste sekundære endepunkter (resurface 1 og 2: PASI 90 ved uge 12 og DLQI ved uge 12 og 28; resurface 2: PASI 75 og PGA ved uge 28) blev analyseret i det fulde datasæt (full analysis set). Det fulde datasæt var i del 1 defineret som alle randomiserede patienter, som modtog mindt én dosis af lægemidlet, mens det i del 2 var defineret som alle patienter, som fuldførte del 1 og påbegyndte del 2, og som modtog mindst én dosis af lægemidlet. Patienter med manglende data blev angivet til at være non-responders (non-responder imputering). I andre sekundære endepunkter, herunder DLQI, blev det fulde sæt af observerede data anvendt, dvs. der blev ikke foretaget imputering af manglende data. VOYAGE 1 (guselkumab) [12] VOYAGE 1 er et randomiseret, dobbeltblindet, placebo- og aktiv komparatorkontrolleret fase 3-studie. 837 patienter med moderat til svær plaque psoriasis, som kandiderede til biologisk behandling, blev randomiseret 2:1:2 til hhv. guselkumab 100 mg (329 patienter), placebo med skift til guselkumab efter 16 uger (174 patienter) og adalimumab doseret iht. produktresuméet (334 patienter). Studiet varede i 48 uger. Studiets primære endepunkter var andelen af patienter, som ved uge 16 opnåede IGA-score 0/1 samt andelen af patienter, som ved uge 16 opnåede PASI 90. Studiets sekundære endepunkter inkluderede PASI 90 efter 48 uger samt andelen af patienter, som ved uge 24 eller 48 opnåede en DLQI-score på 0 eller 1 (ud af de patienter, der havde DLQI > 1 ved baseline). Desuden var andelen af patienter, som opnåede PASI 75 efter 16 uger et sekundært effektmål. Alle randomiserede patienter (intention-to-treat (ITT)-populationen) blev inkluderet ved analyse af de primære (PASI 90 og IGA 0/1 ved uge 16) og nogle af de sekundære endepunkter. Patienter med manglende data blev anset som non-respondere. Bivirkningsprofilen blev analyseret i alle patienter, som modtog mindst én dosis af interventionen. VOYAGE 2 (guselkumab) [13] VOYAGE 2 er et randomiseret, dobbeltblindet, placebo- og aktiv komparatorkontrolleret fase 3-studie patienter indgik i studiet. Patienterne blev randomiseret 2:1:1 til guselkumab 100 mg (n = 496), placebo med skift til guselkumab efter uge 16 (n = 248) eller adalimumab doseret iht. produktresuméet (n = 248). I uge 28 blev patienter i guselkumab-behandling, som havde opnået PASI 90, re-randomiseret 1:1 til behandling med guselkumab eller placebo frem til uge 48. PASI 90 nonrespondere fra adalimumab-gruppen fik guselkumab i uge 28, 32 og hver 8. uge derefter. PASI 90 respondere fra adalimumab-gruppen overgik til placebo i uge 28. Alle patienter blev fulgt i sammenlagt 48 uger. Studiets primære endepunkter var andelen af patienter, som ved uge 16 opnåede IGA-score 0/1 samt andelen af patienter, som ved uge 16 opnåede PASI 90. Studiets sekundære endepunkter inkluderede PASI 90 efter 48 uger samt andelen af patienter, som ved uge 24 eller 48 opnåede en DLQI-score på 0 eller 1 (ud af de patienter, der havde DLQI > 1 ved baseline). Desuden var andelen af patienter, som opnåede PASI 75 efter 16 uger et sekundært effektmål. Analysen af de primære endepunkter (PASI 90 og IGA 0/1 ved uge 16) blev foretaget på alle randomiserede patienter (ITTpopulationen). Patienter, som oplevede behandlingssvigt før uge 16, blev anset som non-respondere ved analyse af uge 16 endepunkter. Bivirkningsprofilen blev analyseret i alle patienter, som modtog mindst én dosis af interventionen. Side 10 af 33

42 Tabel 1: Studiekarakteristika for inkluderede studier til besvarelse af det kliniske spørgsmål Studie [reference] resurface 1 [11] resurface 2 [11] VOYAGE 1 [12] VOYAGE 2 [13] Intervention Komparator NCT-nummer Design Studielande Tildrakizumab Tildrakizumab Guselkumab Guselkumab Placebo og etanercept Placebo og etanercept Placebo og ADA Placebo og ADA NCT NCT NCT NCT Kontrolleret Kontrolleret Kontrolleret Kontrolleret Australien, Canada, Japan, Storbritannien og USA Østrig, Belgien, Canada, Tjekkiet, Danmark, Frankrig, Tyskland, Ungarn, Italien, Israel, Holland, Polen og USA Australien, Canada, Tyskland, Ungarn, Korea, Polen, Rusland, Spanien, Taiwan og USA c Australien, Canada, Tjekkiet, Tyskland, Korea, Polen, Rusland, Spanien og USA c Placebokontrolleret periode (uger) a b b d e a Dette er den initiale placebo-kontrollerede periode. b Publikationen rapporterer kun effekt frem til uge 28. Ved uge 12 blev patienter i placebobehandling randomiseret 1:1 til behandling med tildrakizumab 100 mg eller tildrakizumab 200 mg. Ved uge 28 blev patienter, der havde opnået PASI 50, re-randomiseret til enten samme behandling, anden dosis af tildrakizumab eller placebo. c Studielande jf. Listed Location Countries i studieprotokol på clinicaltrials.gov. d Ved uge 16 kunne patienter overgå til et 32-ugers extension-studie (uge 16-48) med behandling alene med guselkumab. e Ved uge 16 overgik patienter i placebobehandling til behandling med guselkumab. Ved uge 28 blev patienter, der havde opnået PASI 90, re-randomiseret 1:1 til behandling med guselkumab eller placebo frem til uge 48. Samlet behandlingsperiode (uger) Side 11 af 33

43 Population resurface 1 og resurface 2 (tildrakizumab) [11] Inkluderede patienter var voksne ( 18 år) med moderat til svær plaque psoriasis defineret ved baseline BSA 10 %, PASI 12 samt Physician s Global Assessment (PGA) 3. Alle patienter var kandidater til fototerapi eller systemisk behandling. Kvindelige patienter skulle være seksuelt afholdende eller anvende prævention. Eksklusionskriterierne inkluderede graviditet, aktiv eller latent ubehandlet tuberkulose, tidligere behandling med tildrakizumab eller andre IL-23 antagonister samt en række konkurrerende lidelser/sygdomme, herunder infektioner og ukontrollerede systemiske tilstande. I resurface 2 var et yderligere eksklusionskriterie tidligere behandling med etanercept. VOYAGE 1 (guselkumab) [12] Patienter var voksne ( 18 år) med moderat til svær plaque psoriasis i mindst 6 mdr., og som kandiderede til lysbehandling eller systemisk terapi. Patienterne havde ved baseline IGA 3, PASI 12 og BSA 10 %. Eksklusionskriterier inkluderede: andre psoriasisformer end plaque psoriasis; lægemiddelinduceret psoriasis; tidligere behandling med guselkumab eller adalimumab; anti-tnf-hæmmer-behandling de seneste 3 mdr.; anden biologisk behandling de seneste 6 mdr.; systemisk behandling eller lysbehandling de seneste 4 uger; tidligere eller nuværende symptomer på alvorlig, progredierende eller ukontrolleret sygdom (undtaget nonmelanoma hudkræft) i det renale, hepatiske, kardiovaskulære, pulmonale, gastrointestinale, endokrine, neurologiske, hæmatologiske, reumatologiske, psykiatriske eller metaboliske system, der jf. investigator kunne forhindre patienten i at deltage i studiet; graviditet og amning, herunder planlægning af graviditet hos begge køn inden for 5 mdr. efter sidste dosis i studiet; historie af aktiv tuberkulose eller symptomer på tuberkulose. VOYAGE 2 (guselkumab) [13] Patienter var voksne ( 18 år) med moderat til svær plaque-psoriasis med eller uden psoriasis artritis etableret mindst 6 mdr. før første dosering af studiemedicinen. Patienterne havde PASI 12, IGA 3 samt BSA 10 % ved screening og baselinebesøget. Patienterne, som indgik i studiet, var kandidater til lysbehandling eller systemisk behandling. Eksklusionskriterier inkluderede: andre psoriasisformer end plaque psoriasis; lægemiddelinduceret psoriasis; tidligere behandling med guselkumab eller adalimumab; tidligere eller nuværende symptomer på alvorlig, progredierende eller ukontrolleret sygdom (undtaget nonmelanoma hudkræft) i det renale, hepatiske, kardiovaskulære, pulmonale, gastrointestinale, endokrine, neurologiske, hæmatologiske, reumatologiske, psykiatriske eller metaboliske system, der jf. investigator kunne forhindre patienten i at deltage i studiet; graviditet og amning, herunder planlægning af graviditet hos begge køn inden for 5 mdr. efter sidste dosis i studiet; historie af aktiv tuberkulose eller symptomer herpå. Ingen af de fire studier angiver andelen af patienter, der tidligere har oplevet svigt på biologisk behandling generelt eller på biologisk behandling med samme target (IL-23 og IL-12/23). Fagudvalget vurderer, at populationerne i de fire studier er sammenlignelige med den danske patientpopulation ift. bl.a. kropsvægt, sygdomsvarighed og -alvorlighed. Side 12 af 33

44 Tabel 2: Populationskarakteristika for vurderede studier til klinisk spørgsmål 1 Studie [reference] resurface 1 [11] resurface 2 [11] VOYAGE 1 [12] VOYAGE 2 [13] Othsuki [14] Behandlingsarm Placebo Tildrakizumab Placebo Tildrakizumab Placebo Guselkumab Placebo Guselkumab Placebo Guselkumab Patienter, n Alder, år Middelværdi ± SD 47,9 ± 13,5 46,4 ± 13,1 46,4 ± 12,2 44,6 ± 13,6 44,9 ± 12,9 43,9 ± 12,74 43,3 ± 12,4 43,7 ± 12,2 48,3 ± 10,56 47,8 ± 11,07 Range Mænd, n (%) 100 (65) 207 (67) 112 (72) 220 (72) 119 (68,4) 240 (72,9) 173 (69,8) 349 (70,4) 54 (84,4) 47 (74,6) Vægt, kg (middelværdi ± 87,50 ± 88,74 ± 71,56 ± 74,27 ± 88,53 ± 23,87 89,35 ± 22,12 NA NA NA NA SD) 26,04 22,73 14,01 16,04 BMI (middelværdi ± SD) NA NA NA NA 28,9 ± 6,9 29,7 ± 6,22 29,6 ± 6,6 29,6 ± 6,5 25,42 ± 4,79 26,33 ± 5,03 Sygdomsvarighed, år 13,66 ± NA NA NA NA 17,6 ± 12,4 17,9 ± 12,27 17,9 ± 11,9 17,9 ± 12,0 (middelværdi ± SD) 10,29 14,39 ± 9,23 BSA, %-involvering af 29,6 ± 31,3 ± 29,7 ± 17,44 kroppen (middelværdi ± SD) 17,28 14,75 34,2 ± 18,44 25,8 ± 15,9 28,3 ± 17,10 28,0 ± 16,5 28,5 ± 16,4 33,6 ± 18,39 37,9 ± 21,48 PASI-score (middelværdi ± 25,92 ± 26,73 ± 19,3 ± 7,07 20,0 ± 7,85 20 ± 7,57 20,5 ± 7,63 20,4 ± 8,7 22,1 ± 9,49 21,5 ± 8,0 21,9 ± 8,8 SD) 12,34 12,20 DLQI-score (middelværdi ± SD) 13,2 ± 7,25 13,9 ± 6,68 13,7 ± 6,98 14,8 ± 7,24 13,3 ± 7,1 14,0 ± 7,48 15,1 ± 7,2 14,7 ± 6,9 10,6 ± 7,74 10,3 ± 7,27 Psoriasis-artritis, n (%) NA NA NA NA 30 (17,2) 64 (19,5) 46 (18,5) 89 (17,9) 10 (15,6) 10 (15,9) Tidl. systemisk behandling, n (%) NA NA NA NA 92 (52,9) 210 (63,8) 149 (60,1) 331 (66,7) 38 (59,4) 37 (58,7) Tidl. biologisk behandling, n (%) 35 (23) 71 (23) 20 (13) 39 (13) 34 (19,5) 71 (21,6) 54 (21,8) 101 (20,4) 10 (15,6) 11 (17,5) BMI: Body mass index; BSA: Body surface area; DLQI: Dermatology Life Quality Index; PASI: Psoriasis Area and Severity Index. n = 63. Diagnosis based on Classification Criteria for Psoriatic Arthritis. Side 13 af 33

45 9.1.2 Resultater og vurdering Resultater og vurdering af de effektmål, som fagudvalget har præspecificeret som hhv. kritiske og vigtige, følger nedenfor. PASI 75 (kritisk) PASI er et valideret mål for sværhedsgraden af kronisk plaque psoriasis, der kombinerer areal og læsionernes sværhedsgrad. PASI 75 er reduktion i PASI-værdi med 75 % i forhold til baseline. Tabel 3. Vurdering af klinisk merværdi: PASI 75 ved uge Forhåndsdefineret grundlag for vurdering Resultater Absolutte forskelle 15 procentpoint forskel i respons 0,0 [-38,8; 67,8] procentpoint Relative forskelle Stor merværdi Nedre konfidensgrænse > 1,33 og risiko 5 % Vigtig merværdi Nedre konfidensgrænse > 1,11 Lille merværdi Nedre konfidensgrænse > 1,00 og < 1,11 Ingen merværdi Nedre konfidensgrænse < 1,00 1,00 [0,57; 1,75] og øvre konfidensgrænse > 1 Negativ merværdi Øvre konfidensgrænse < 1 Evidensens kvalitet Moderat I resurface 1 opnåede 74 % (229/309) og 6 % (9/155) af patienterne i behandling med hhv. tildrakizumab og placebo PASI 75 ved uge 28. I resurface 2 var andelen af patienter 70 % (216/307) og 6 % (9/156) for hhv. tildrakizumab og placebo [11]. I VOYAGE 1 opnåede 91 % (300/329) og 6 % (10/174) af patienterne i behandling med hhv. guselkumab og placebo PASI 75 ved uge 24 [12], mens det samme var tilfældet for hhv. 89 % (442/496) og 8 % (20/248) i VOYAGE 2 [13]. Baseret på den indirekte statistiske sammenligning ved uge er der beregnet en absolut forskel mellem tildrakizumab og guselkumab på 0,0 procentpoint. Den mindste klinisk relevante forskel på 15 procentpoint er dermed ikke opnået. Den relative forskel er på 1,00 (0,57; 1,75), hvilket svarer til ingen merværdi ud fra de forhåndsdefinerede væsentlighedskriterier, idet den nedre grænse for konfidensintervallet er < 1, og den øvre grænse er > 1. Fagudvalget bemærker, at en større andel af de patienter, der får guselkumab i VOYAGE-studierne, opnår PASI 75, sammenlignet med andelen af patienter, som opnår PASI 75 i resurface-studierne. I VOYAGE 2-studiet er der dog også flere af patienterne i placebo-armen, som opnår PASI 75. Den meta-analyserede relative risiko for henholdsvis guselkumab vs. placebo (12,5, 95 % CI: [9,09; 16,67]) og tildrakizumab vs. placebo (12,5, 95 % CI: [7,69; 20,0]) er ens. Sammenlagt bliver der derfor ingen forskel mellem lægemidlerne i den indirekte analyse. Samlet vurderer fagudvalget, at tildrakizumab har ingen klinisk merværdi vedr. PASI 75 sammenlignet med guselkumab (moderat evidenskvalitet). Side 14 af 33

46 PASI 90 (vigtig) PASI 90 er reduktion i PASI-værdi med 90 %. Det ideelle langsigtede behandlingsmål for patienter med hudpsoriasis er en fuldstændig eller næsten fuldstændig afglatning af huden, hvorfor det er relevant også at lægge data for PASI 90 til grund for vurdering af klinisk effekt. Tabel 4. Vurdering af klinisk merværdi: PASI 90 ved uge Forhåndsdefineret grundlag for vurdering Medicinrådets vurdering Absolutte forskelle 15 procentpoint forskel i respons -14,4 procentpoint [-53.9; 90,6] Relative forskelle Stor merværdi Nedre konfidensgrænse > 1,33 og risiko 5 % Vigtig merværdi Nedre konfidensgrænse > 1,11 Evidensens kvalitet Lille merværdi Nedre konfidensgrænse > 1,00 og <1,11 Ingen merværdi Nedre konfidensgrænse < 1,00 og Øvre konfidensgrænse > 1 Negativ merværdi Øvre konfidensgrænse < 1 Moderat 0,81 [0,30; 2,17] I resurface 1 opnåede 48 % (147/309) og 3 % (4/155) af patienterne i behandling med hhv. tildrakizumab og placebo PASI 90 ved uge 28. I resurface 2 var andelen af patienter 52 % (161/307) og 1 % (2/156) for hhv. tildrakizumab og placebo [11]. I VOYAGE 1 opnåede 80 % (264/329) og 3 % (5/174) af patienterne i behandling med hhv. guselkumab og placebo PASI 90 ved uge 24 [12], mens det samme var tilfældet for hhv. 75 % (373/496) og 2 % (6/248) i VOYAGE 2 [13]. Baseret på den indirekte statistiske sammenligning ved uge er der beregnet en absolut forskel mellem tildrakizumab og guselkumab på -14,4 procentpoint til fordel for guselkumab. Den mindste klinisk relevante forskel på 15 procentpoint er dermed ikke opnået. Den relative forskel er på 0,81 (0,30; 2,17), hvilket svarer til ingen merværdi ud fra de forhåndsdefinerede væsentlighedskriterier, idet den nedre grænse for konfidensintervallet er < 1, og den øvre grænse er > 1. Samlet vurderer fagudvalget, at tildrakizumab har ingen klinisk merværdi vedr. PASI 90 sammenlignet med guselkumab (moderat evidenskvalitet). Livskvalitet målt ved DLQI (vigtig) For både tildrakizumab og guselkumab blev livskvalitet målt ved DLQI-spørgeskemaet. Fagudvalget havde i protokollen defineret den mindste klinisk relevante forskel som 15 procentpoint forskel i respons på andelen af patienter, som opnåede en DLQI-score på 0-1. Tabel 5. Vurdering af klinisk merværdi: Livskvalitet målt ved DLQI 0-1 ved uge Forhåndsdefineret grundlag for vurdering Medicinrådets vurdering Absolutte forskelle 15 procentpoint forskel i respons -30,6 procentpoint [-43,8; -4,8] Evidensens kvalitet Moderat Side 15 af 33

47 I resurface 1 opnåede 49 % (152/309) og 5 % (8/155) af patienterne i behandling med hhv. tildrakizumab og placebo DLQI 0-1 ved uge 28. I resurface 2 var dette tilfældet for 51 % (157/307) og 8 % (12/156) af patienterne i behandling med hhv. tildrakizumab og placebo [11]. I VOYAGE 1 opnåede 59 % (195/329) og 4 % (7/174) af patienterne i behandling ved hhv. guselkumab og placebo DLQI 0-1 ved uge 24 [12], mens det samme var tilfældet for hhv. 57 % (283/496) og 3 % (8/248) i VOYAGE 2 [13]. Baseret på den indirekte statistiske sammenligning ved uge er der beregnet en absolut forskel mellem tildrakizumab og guselkumab på -30,6 % til fordel for guselkumab. Den mindste klinisk relevante forskel på 15 % er dermed opnået. Fagudvalget bemærker dog, at i VOYAGE-studierne ekskluderes patienter med baseline DLQI = 0-1 i analysen af uge 24 data, mens dette ikke er tilfældet i resurface-studierne. Denne eksklusion stiller guselkumab dårligere ved sammenligningen med tildrakizumab ved uge Ydermere betoner fagudvalget, at DLQI ikke er et optimalt redskab til måling af livskvalitet for psoriasispatienter, og at der derfor tages konservativt forbehold for dette. Fagudvalget vurderer på denne baggrund, at tildrakizumab har en negativ klinisk merværdi vedr. livskvalitet sammenlignet med guselkumab (moderat evidenskvalitet). Alvorlige uønskede hændelser (SAEs) (kritisk) SAEs omfatter enhver alvorlig hændelse eller bivirkning opstået i de kliniske studier ved behandling med lægemidlet. Tabel 6. Vurdering af klinisk merværdi: Alvorlige uønskede hændelser (SAEs) ved uge Forhåndsdefineret grundlag for vurdering Medicinrådets vurdering Absolutte forskelle 5 procentpoint forskel -1,0 procentpoint [-3,0;8,8] Stor merværdi Øvre konfidensgrænse < 0,75 og Relative forskelle risiko 5 % Vigtig merværdi Øvre konfidensgrænse < 0,90 Lille merværdi Øvre konfidensgrænse < 1,00 Ingen merværdi Øvre konfidensgrænse > 1 0,72 [0,15;3,45] Negativ merværdi Nedre konfidensgrænse > 1 Evidensens kvalitet Lav ANM: Første kolonne indeholder de i protokollen og metodehåndbogen præspecificerede grundlag for vurderingen. Anden kolonne indeholder data fra ansøgningen, som indgår i Medicinrådets vurdering. I resurface 1 blev der ved uge 28 registreret SAEs for 4 % (11/309) og 1% (1/155) af patienterne i behandling med hhv. tildrakizumab og placebo. Det samme gjorde sig gældende for hhv. 4 % (13/307) og 3 % (4/156) af patienterne i resurface 2 [11]. I VOYAGE 2 havde 4 % (18/496) og 1 % (3/248) af patienterne i behandling med hhv. guselkumab og placebo oplevet SAEs ved uge 28 [13]. SAEs blev ikke rapporteret i VOYAGE 1. Baseret på den indirekte statistiske sammenligning ved uge er der beregnet en absolut forskel mellem tildrakizumab og guselkumab på -1,0 procentpoint. Dermed oplevede 1,0 procentpoint færre patienter i behandling med tildrakizumab alvorlige uønskede hændelser sammenlignet med patienter i behandling med guselkumab. Den mindste klinisk relevante forskel på 5 procentpoint er dog ikke opnået. Den relative forskel er på 0,72 (0,15; 3,45), hvilket svarer til ingen merværdi ud fra de forhåndsdefinerede væsentlighedskriterier, idet den nedre grænse for konfidensintervallet er < 1, og den øvre grænse er > 1. Side 16 af 33

48 Fagudvalget bemærker, at SAEer i resurface 1 og 2 er opgjort som antallet af patienter med mindst én SAE i to tidsintervaller (uge 0-16 og uge 17-28) [11]. Patienter, som oplevede mindst én SAE i hvert af de to tidsintervaller, bliver derfor talt dobbelt i den samlede opgørelse af SAEs, hvilket stiller tildrakizumab dårligere i den statistiske sammenligning. Samlet vurderer fagudvalget, at tildrakizumab har ingen klinisk merværdi vedr. alvorlige uønskede hændelser sammenlignet med guselkumab (lav evidenskvalitet). Behandlingsophør (vigtig) Behandlingsophør reflekterer, hvor mange patienter som afbryder behandlingen i de kliniske studier uanset årsag, herunder bivirkninger og manglende effekt. Effektmålet er medtaget som indikator for behandlingskvalitet og tolerancen ved langtidsbehandling. I den endelige ansøgning ses der en betydelig heterogenitet (84,5 %) ift. graden af behandlingsophør mellem placebo-armene i resurface 1 (0,13 %) og resurface 2 (0,06 %) ved uge 28. Ansøger har indsendt analyser baseret på to forskellige statistiske modeller, fixed effects modellen der anvendes hvis der ikke er tegn på heterogenitet, og random effects modellen der anvendes hvis der er heterogenitet. Dermed anvendes analysen der er baseret på random effects modellen i vurderingen af dette effektmål. Tabel 7. Vurdering af klinisk merværdi: Behandlingsophør ved uge Forhåndsdefineret grundlag for vurdering Medicinrådets vurdering Absolutte forskelle 15 procentpoint forskel 1,2 procentpoint [-1,9;13,2] Stor merværdi Øvre konfidensgrænse < 0,75 og Relative forskelle risiko 5 % Vigtig merværdi Øvre konfidensgrænse < 0,90 Lille merværdi Øvre konfidensgrænse < 1,00 Ingen merværdi Øvre konfidensgrænse > 1 1,41 [0,36;5,56] Negativ merværdi Nedre konfidensgrænse > 1 Evidensens kvalitet Meget lav I resurface 1 blev der ved uge 28 registreret behandlingsophør for 13 % (41/309) og 6 % (9/155) af patienterne i behandling med hhv. tildrakizumab og placebo. I resurface 2 var dette tilfældet for hhv. 6 % (18/307) og 9 % (14/156) af patienterne [11]. I VOYAGE 2 blev der ved uge 28 registreret behandlingsophør for 5 % (26/496) og 6 % (15/248) af patienterne i behandling med hhv. guselkumab og placebo [13]. Behandlingsophør blev ikke registreret i VOYAGE 1. Baseret på den indirekte statistiske sammenligning ved uge er der beregnet en absolut forskel mellem tildrakizumab og guselkumab på 1,2 % til fordel for guselkumab. Den mindste klinisk relevante forskel på 15 % er dermed ikke opnået. Den relative forskel er 1,41 (0,36; 5,56), hvilket svarer til ingen merværdi ud fra de forhåndsdefinerede væsentlighedskriterier, idet den nedre grænse for konfidensintervallet er < 1, og den øvre grænse er > 1. Samlet vurderer fagudvalget, at tildrakizumab har ingen klinisk merværdi vedr. behandlingsophør sammenlignet med guselkumab (meget lav evidenskvalitet). Side 17 af 33

49 PASI 90 i subpopulationer (vigtig) For subpopulationerne af patienter med tidligere behandlingssvigt på biologiske lægemidler generelt samt specifikt på lægemidler med hhv. IL-23 og IL-12/23-target, ønsker fagudvalget at vurdere, om behandling med tildrakizumab har den ønskede effekt. En effekt af tildrakizumab i disse populationer vil potentielt betyde flere behandlingsmuligheder for patienterne. Ansøger angiver dog, at der ikke foreligger publicerede data for de to subpopulationer. På denne baggrund vurderer fagudvalget, at den tilgængelige evidens ikke tillader en vurdering af den kliniske merværdi af tildrakizumab for subpopulationerne af patienter med behandlingssvigt på et biologisk lægemiddel generelt eller på et biologisk lægemiddel med samme target Evidensens kvalitet Evidensens kvalitet for voksne ( 18 år) med moderat til svær plaque psoriasis er samlet set vurderet som værende lav, da evidensens kvalitet for det laveste vurderede kritiske effektmål, er lav. Overvejelser vedrørende evidensens kvalitet kan ses i bilag 1. Indledningsvist blev lægemidlernes direkte sammenligninger med placebo vurderet. Overordnet var alle studier af høj kvalitet, og der blev ikke nedgraderet for risiko for bias (se bilag 1). For alvorlige uønskede hændelser (SAEs) blev evidensens kvalitet nedjusteret for Imprecision, da konfidensintervallet er bredt og inkluderer både negativ og positiv merværdi. For effektmålet behandlingsophør er der nedjusteret både for Inconsistency (heterogeniteten i meta-analysen var høj) og for Imprecision (konfidensintervallet er bredt og inkluderer både negativ og positiv merværdi). Da merværdien af tildrakizumab sammenlignet med guselkumab er vurderet via indirekte sammenligninger med placebo som fælles komparator, er der for alle effektmål nedjusteret for Indirectness Konklusion for voksne ( 18 år) med moderat til svær plaque psoriasis Fagudvalget vurderer, at tildrakizumab giver en ingen klinisk merværdi for voksne ( 18 år) med moderat til svær plaque psoriasis (lav evidenskvalitet). Effektmål Vigtighed Aggregeret kategori Evidenskvalitet PASI 75 Kritisk Ingen klinisk merværdi Moderat PASI 90 Vigtig Ingen klinisk merværdi Moderat Livskvalitet Vigtig Negativ klinisk merværdi Moderat Alvorlige uønskede hændelser Kritisk Ingen klinisk merværdi Lav Behandlingsophør Vigtig Ingen klinisk merværdi Meget lav PASI 90 Svigt på biologisk lægemiddel generelt Vigtig Kan ikke vurderes Kan ikke vurderes Side 18 af 33

50 PASI 90 Vigtig Kan ikke vurderes Kan ikke vurderes Svigt på biologisk lægemiddel med samme target Samlet kategori Ingen klinisk merværdi Lav I den samlede vurdering vægter fagudvalget, at der ikke er fundet klinisk relevante forskelle mellem tildrakizumab og guselkumab for de kritiske effektmål PASI 75 og SAEs samt for de vigtige effektmål PASI 90 og behandlingsophør. Fagudvalget bemærker, at ansøger som komparator har valgt guselkumab, som er en anden IL-23-hæmmer og er blandt de mest effektive psoriasis-præparater på markedet. For det vigtige effektmål livskvalitet vurderer fagudvalget, at tildrakizumab giver en negativ klinisk merværdi sammenlignet med guselkumab. Fagudvalget bemærker dog, at DLQI er et generelt dermatologisk redskab, som ikke er optimalt til måling af psoriasis-specifikke gener. Vurderingen af dette effektmål er derfor forbundet med en vis usikkerhed. Fagudvalget vurderer samlet set, at tildrakizumab og guselkumab har sammenlignelig effekt, og at tildrakizumab har ingen klinisk merværdi sammenlignet med guselkumab. Evidenskvaliteten er lav for det kritiske effektmål alvorlige uønskede hændelser, dermed er den samlede evidenskvalitet ligeledes vurderet at være lav. 10 Andre overvejelser Ansøger har leveret oplysninger om de lægemiddelhåndteringsmæssige forhold, som specificeret i protokollen for tildrakizumab: Mulighed for behandlingspause. Mulighed for dosisreduktion/behandlingsintervalforlængelse. Fagudvalget ønsker specifikt en uddybning af 200 mg doseringsgruppen ( patienter med specifikke karakteristika bl.a. høj sygdomsbyrde og kropsvægt 90 kg ), herunder om der er forskelle i behandlingseffekt i forhold til 100 mg doseringen, og hvad der forstås ved høj sygdomsbyrde. Derudover ønsker fagudvalget en estimering af andelen af patientpopulationen, som forventes at tilhøre gruppen med behov for 200 mg dosering. Forhold mellem initialdosis og vedligeholdelsesdosis. Vedligeholdelse af effekt mellem doseringer hver 12. uge. Samlet set vurderer fagudvalget, at oplysninger om disse forhold ikke påvirker kategoriseringen af den kliniske merværdi af tildrakizumab. Vurderingen af de enkelte forhold er belyst nedenfor: Mulighed for behandlingspause Der er ikke publiceret specifikke undersøgelser af mulighed for behandlingspause. Ansøger har indsendt upublicerede data til at besvare dette forhold, så disse er ikke indgået i fagudvalgets vurdering af tildrakizumab. Fagudvalget kan derfor ikke forholde sig til muligheden for behandlingspause ved behandling med tildrakizumab. Side 19 af 33

51 Mulighed for dosisreduktion/behandlingsintervalforlængelse Der foreligger ikke publicerede data fra resurface-studierne for dosisreduktion eller behandlingsintervalforlængelse ift. indikationen for tildrakizumab på 100 mg. Ansøger henviser dog til et fase 2b-studie (NCT [15]), hvor PASI 75 respondere ved uge 16 blev re-randomiseret til behandling med tildrakizumab 100 mg hver 12. uge eller tildrakizumab 25 mg hver 12. uge. Andelen af patienter, som ved uge 52 havde bibeholdt PASI 75 var 97 % og 70 % for hhv. tildrakizumab 100 mg og 25 mg, og forskellen i effekt mellem de to doser var statistisk signifikant (p < 0,005). Fagudvalget bemærker, at der er en stor del af patienterne, der har effekt på den lave dosis, og fagudvalget kunne have ønsket at se data for en dosis på 50 eller 75 mg. hver 12. uge Ift. administration af 200 mg til patienter med specifikke karakteristika (høj sygdomsbyrde eller kropsvægt > 90 kg) angiver ansøger, at der i den generelle patientpopulation i fase 3-studierne ikke er påvist signifikante forskelle i hverken behandlingseffekt eller bivirkningsprofil ved behandling med tildrakizumab 100 mg sammenlignet med tildrakizumab 200 mg. Definitionen af høj sygdomsbyrde er ikke klart angivet i hverken produktinformationen eller EPAR en for tildrakizumab [10,16]. I EPAR en angives det, at der ud fra farmakokinetiske studier ikke sås en sammenhæng mellem øget dosering af tildrakizumab og forbedret klinisk respons [16]. Ansøger har desuden indsendt upublicerede data til besvarelse af dette forhold, så disse er ikke indgået i fagudvalgets vurdering af tildrakizumab. I forhold til dosisreduktion/behandlingsintervalforlængelse anbefaler fagudvalget at følge indikation for tildrakizumab, da der ikke er tilstrækkelige data for andre doseringsregimer. Forhold mellem initialdosis og vedligeholdelsesdosis Ansøger angiver, at den anbefalede dosis for tildrakizumab (100 mg ved uge 0, 4 og hver 12. uge derefter) blev fastlagt på baggrund af fase 2 og 3-studier [11,15], som viste den mest optimale behandlingseffekt ved behandling ved disse tidsintervaller. Data fra fase 2-studiet [15] såvel som halveringstiden for tildrakizumab (23,4 dage [16]) viste, at en hyppig dosering resulterede i hurtig behandlingseffekt. På denne baggrund blev en loading dosis ved uge 4 fastlagt. De to fase 3-studier [11] har fundet den anbefalede dosering både optimal, effektiv og sikker, og ansøger angiver, at lignende data ikke er tilgængeligt for en lavere doseringshyppighed inden for de første 12 uger af behandlingen. Ansøger angiver endvidere, at med en halveringstid på 23,4 dage er en vedligeholdelsesdosis på tildrakizumab 100 mg nok til at holde serumkoncentrationer på det terapeutiske niveau. Dog er længere tids behandling nødvendig for at opnå det terapeutiske niveau, hvis der udelukkende gives en vedligeholdelsesdosis. Dosering i uge 4 resulterer i en fordobling af plasmaniveauer og dalværdier, hvilket svarer til niveauerne i steady state (defineret ved, at udskillelsen af lægemidlet er lig med indtagelsen). I forhold til forholdet mellem initialdosis og vedligeholdelsesdosis angiver ansøger, at den anbefalede dosering ved uge 4 og 12 resulterer i den mest optimale effekt i hhv. initial- og vedligeholdelsesfasen. Fagudvalget er enige i dette, da der ikke er tilstrækkelige data på andre doseringsregimer. Vedligeholdelse af effekt mellem doseringer hver 12. uge Der er ikke publiceret data, der beskriver vedligeholdelsen af effekt mellem doseringer hver 12. uge. Fagudvalget kan derfor ikke forholde sig til vedligeholdelse af effekt mellem doseringer hver 12. uge ved behandling med tildrakizumab. Side 20 af 33

52 11 Fagudvalgets vurdering af samlet klinisk merværdi og samlet evidensniveau Fagudvalget vurderer, at tildrakizumab til voksne ( 18 år) patienter med moderat til svær plaque psoriasis, som er kandidater til 2. generations immunmodulerende behandling (behandling med biologiske lægemidler) og ikke har psoriasisartropati giver: Ingen klinisk merværdi til patienter med moderat til svær plaque psoriasis sammenlignet med guselkumab. Evidensens kvalitet vurderes at være lav. Den kliniske merværdi kan ikke vurderes for subpopulationen af patienter med tidligere behandlingssvigt på biologiske lægemidler generelt. Den kliniske merværdi kan ikke vurderes for subpopulationen af patienter med tidligere behandlingssvigt på biologiske lægemidler med samme target. 12 Rådets vurdering af samlet klinisk merværdi og samlet evidensniveau Medicinrådet vurderer, at tildrakizumab til voksne ( 18 år) patienter med moderat til svær plaque psoriasis, som er kandidater til 2. generations immunmodulerende behandling (behandling med biologiske lægemidler) og ikke har psoriasisartropati giver: Ingen klinisk merværdi til patienter med moderat til svær plaque psoriasis sammenlignet med guselkumab. Evidensens kvalitet vurderes at være lav. Den kliniske merværdi kan ikke vurderes for subpopulationen af patienter med tidligere behandlingssvigt på biologiske lægemidler generelt. Den kliniske merværdi kan ikke vurderes for subpopulationen af patienter med tidligere behandlingssvigt på biologiske lægemidler med samme target. 13 Relation til eksisterende behandlingsvejledning Der foreligger en behandlingsvejledning fra RADS fra 2016 for dette terapiområde [6]. Medicinrådet har endnu ingen terapivejledning på området. Den eksisterende RADS-behandlingsvejledning hviler på en netværksmetaanalyse, som ikke inkluderer tildrakizumab. Indtil en fornyet metaanalyse er udarbejdet, må tildrakizumab med baggrund i vurderingen i forhold til komparatoren guselkumab anses for at udgøre et klinisk ligestillet alternativ til adalimumab, secukinumab, ixekizumab og ustekinumab, som aktuelt alle anbefales som 1. linjebehandlinger til psoriasis uden ledgener samt guselkumab, brodalumab og certolizumab pegol, som er anbefalet af Medicinrådet. Dette er begrundet med samme effekt på hudsymptomer og sammenlignelig bivirkningsprofil. Side 21 af 33

53 14 Referencer 1. Sundhedsstyrelsen. Kommissorium for udarbejdelse af national klinisk retningslinje for psoriasis. Sekretariatet for nationale kliniske retningslinjer Griffiths CEM, Barker JNWN. Pathogenesis and clinical features of psoriasis. Lancet (London, England). 2007;370(9583): Finlay AY. Current severe psoriasis and the Rule of Tens. Br J Dermatol. 2005;152(5): DDS (Dansk Dermatologisk Selskab). Retningslinjer for behandling af psoriasis med 2. generations immunomodulatorisk behandling Dermbio (Database for Biologisk Behandling i Dermatologi). Dermbio Årsrapport 2017 [internet] Tilgængelig fra: 6. RADS (Rådet for Anvendelse af Dyr Sygehusmedicin). Baggrundsnotat for 2. generations immunmodulerende lægemidler til behandling af psoriasis. 2016; 7. WHO (World Health Organization). Global Report on Psoriasis. 2016; DDS (Dansk Dermatologisk Selskab). Retningslinjer for behandling af psoriasis med 2.generations immunmodulatorisk behandling Medicinrådet. Lægemiddelrekommandation for lægemidler til behandling af psoriasis [internet]. Tilgængelig fra: EMA. Tildrakizumab, Ilumetri produktresumé. Senest opdateret 9. oktober 2018 [internet]. Tilgængelig fra: _Product_Information/human/000697/WC pdf 11. Reich K, Papp KA, Blauvelt A, Tyring SK, Sinclair R, Thaçi D, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (resurface 1 and resurface 2): results from two randomised controlled, phase 3 trials. Lancet. 2017;390(10091): Blauvelt A, Papp KA, Griffiths CEM, Randazzo B, Wasfi Y, Shen Y-K, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-. J Am Acad Dermatol. 2017;76(3): Reich K, Armstrong AW, Foley P, Song M, Wasfi Y, Randazzo B, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, p. J Am Acad Dermatol. 2017;76(3): Ohtsuki M, Kubo H, Morishima H, Goto R, Zheng R, Nakagawa H. Guselkumab, an anti-interleukin- 23 monoclonal antibody, for the treatment of moderate to severe plaque-type psoriasis in Japanese patients: Efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study. J Dermatol. 2018;45(9): Papp K, Thac D, Reich K, Riedl E, Langley RG, Krueger JG, et al. Tildrakizumab ( MK-3222 ), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebocontrolled trial. Br J Dermatol. 2015; EMA. Tildrakizumab, Ilumetri EPAR. Senest opdateret 9. oktober 2018 [internet]. Tilgængelig fra: Side 22 af 33

54 15 Sammensætning af fagudvalg og kontaktinformation til Medicinrådet Medicinrådets fagudvalg vedrørende psoriasis og psoriasis med ledgener Forvaltningslovens 4, stk. 2, har været anvendt i forbindelse med udpegning af medlemmer til dette fagudvalg. Formand Diljit Kaur Knudsen Speciallæge Medlemmer Trine Høgsberg Afdelingslæge Dermatologi ikke repræsenteret Sumangali Chandra Prasad Speciallæge Kan ikke udpege en kandidat, der opfylder Medicinrådets habilitetskrav Lone Skov Klinisk professor, overlæge Thomas Loof Hedegård Farmaceut Maija Bruun Haastrup Klinisk farmakolog Eli Glückstadt Patient/patientrepræsentant Andreas H.M. Jensen Patient/patientrepræsentant Indstillet af Lægevidenskabelige Selskaber Udpeget af Region Midtjylland Region Nordjylland Region Syddanmark Region Sjælland Region Hovedstaden Dansk Selskab for Sygehusapoteksledelse Dansk Selskab for Klinisk Farmakologi Danske Patienter Danske Patienter Tidligere medlemmer, som har taget del i processen: Lars Erik Bryld, overlæge, ph.d. og Lars Iversen, professor. Medicinrådets sekretariat Medicinrådet Dampfærgevej 27-29, 3. th København Ø medicinraadet@medicinraadet.dk Sekretariatets arbejdsgruppe: Jeppe Schultz Christensen (projekt- og metodeansvarlig) Mette Hollensted (projektdeltager) Madina Saidj (projektdeltager) Ilse Linde (fagudvalgskoordinator) Jan Odgaard-Jensen (biostatistiker) Bettina Fabricius Skov Christensen (informationsspecialist) Kirsten Holdt Henningsen (teamleder) Side 23 af 33

55 Versionslog Version Dato Ændring Godkendt af Medicinrådet. Side 24 af 33

56 16 Bilag 1: GRADE-evidensprofiler Cochrane Risk of Bias Risiko for bias er vurderet for alle studier til besvarelse af det kliniske spørgsmål. Studiernes risiko for bias er vurderet ved brug af tjeklisten Cochrane Risk of Bias tool (Cochrane handbook version 5.1 del 2.8, se resurface 1 Risiko for bias for studie: resurface 1 (NCT ) Reich et al., 2017 [11] Bias Selection bias Risk of bias Elaboration Random sequence generation Low Up to week 28 (part 1 and 2): In part 1, patients were randomized in a 2:2:1 ratio to receive one of the three treatments: tildrakizumab 200 mg, tildrakizumab 100 mg or placebo. In part 2, the patients receiving active substances in part 1 continued with their treatment, while the patients receiving placebo were re-randomized to either tildrakizumab 200 mg or tildrakizumab 100 mg. Allocation concealment Low The contract research organization (Parexel) generated computer-generated randomization sequences, and an interactive voice-response system and interactive web-response system was used by Parexel to allocate participants to groups. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Performance bias: blinding of participants and personnel. Assessment made for class of outcomes. Patient-reported outcomes: PASI, DLQI Objective outcomes: Adverse events, Withdrawal irrespective of reason Low Low A double-masking technique was used, in which tildrakizumab and its matching placebo were identical in appearance and packaging. Additional placebo doses were administered to maintain masking. Ibid. Detection bias: blinding of outcome assessment. Assessment made for class of outcomes. Patient-reported outcomes: PASI, DLQI Objective outcomes Adverse events, Withdrawal irrespective of reason Attrition bias: incomplete outcome data. Assessment made for class of outcomes. Reporting bias: selective reporting outcome data. Low Low Low Low The team doing the analysis was blinded until the database was locked (while no interim analyses were done). Ibid. 772 patients underwent randomization, while over 96 % (744 patients) completed the part 1 and 88 % (676 patients) completed the part 2. Nothing suggests reporting bias due to selective outcome reporting, cf. clinicaltrials.gov. Other bias Low No other concern regarding potential risk of bias. Overall bias Low Overall risk of bias judged low. Side 25 af 33

57 resurface 2 Risiko for bias for studie: resurface 2 (NCT ) Reich et al., 2017 [11] Bias Selection bias Risk of bias Elaboration Random sequence generation Low Up to week 28 (part 1 and 2): In part 1, patients were randomized in a 2:2:1:2 ratio to receive one of the four treatments: tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg. In part 2, the placebo group was re-randomised (1:1) to tildrakizumab 200 mg or 100 mg, while the patients receiving active substances in part 1 continued with their treatment. Allocation concealment Low The contract research organization (Parexel) generated computer-generated randomization sequences, and an interactive voice-response system and interactive web-response system was used by Parexel to allocate participants to groups. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Performance bias: blinding of participants and personnel. Assessment made for class of outcomes. Patient-reported outcomes: PASI, DLQI Low A double-masking technique was used, in which tildrakizumab and its matching placebo or etanercept and its matching placebo were identical in appearance and packaging. Additional placebo doses were administered to maintain masking. Objective outcomes: Adverse events, Withdrawal irrespective of reason Low Ibid. Detection bias: blinding of outcome assessment. Assessment made for class of outcomes. Patient-reported outcomes: PASI, DLQI Objective outcomes Adverse events, Withdrawal irrespective of reason Attrition bias: incomplete outcome data. Assessment made for class of outcomes. Reporting bias: selective reporting outcome data. Low Low Low Low The team doing the analysis was blinded until the database was locked (while no interim analyses were done). Ibid patients underwent randomization, while over 98 % (1076 patients) completed the part 1 and 91 % (995 patients) completed the part 2. Nothing suggests reporting bias due to selective outcome reporting, cf. clinicaltrials.gov. Other bias Low No other concern regarding potential risk of bias. Overall bias Low Overall risk of bias judged low. Side 26 af 33

58 VOYAGE 1 Risiko for bias for studie: VOYAGE 1 (NCT ) Blauvelt et al., 2017 [12] Bias Selection bias Risk of bias Elaboration Random sequence generation Allocation concealment Low Low Patients were randomly assigned in a 2:1:2 ratio to receive guselkumab, placebo followed by guselkumab or adalimumab. Randomization generated via permuted block method. Central randomization was implemented using an interactive www response system. Performance bias: blinding of participants and personnel. Assessment made for class of outcomes. Patient-reported Low To maintain the blind, matching placebos were used. outcomes: PASI, DLQI Objective outcomes: Adverse events, Withdrawal irrespective of reason Low Ibid. Detection bias: blinding of outcome assessment. Assessment made for class of outcomes. Patient-reported outcomes: PASI, DLQI Objective outcomes Adverse events, Withdrawal irrespective of reason Attrition bias: incomplete outcome data. Assessment made for class of outcomes. Low Low Unclear Nothing suggest blinding was unveiled during study. Ibid. All randomized patients were included in the primary and secondary efficacy analyses; data analyzed by randomized treatment group. Safety analyses included all patients who received 1 dose of guselkumab. Patients who discontinued study agent due to lack of efficacy or an AE worsening or who started a protocol-prohibited psoriasis treatment were considered nonresponders (binary endpoints) or had baseline values carried over (continuous endpoints). Other patients with missing data were considered nonresponders for binary endpoints (non-responder imputation). Because of insufficient information on procedure and multiple imputation not used, risk of bias is judged unclear. Reporting bias: selective reporting outcome data. Low DLQI response was specifically analyzed for patients with DLQI > 1 at baseline (n = 320 for guselkumab, n = 319 for adalimumab), as pre-specified in study protocol (clinicaltrials.gov). We consider this to be a deviation from standard good practice, however due to only few patients being excluded from these analyses (3-4,5 %) we do not consider that it has affected the results substantially. Nothing suggests reporting bias due to selective outcome reporting, cf. clinicaltrials.gov. Other bias Low No other concern regarding potential risk of bias. Overall bias Low Overall risk of bias judged low. Side 27 af 33

59 VOYAGE 2 Risiko for bias for studie: VOYAGE 2 NCT Reich et al., 2017 [13] Bias Selection bias Risk of bias Elaboration Random sequence generation Allocation concealment Low Low Patients were randomized 2:1:1 to guselkumab; placebo followed by guselkumab; or adalimumab. At week 28, guselkumab-treated patients achieving PASI 90 (responders) were rerandomized in a 1:1 ratio to guselkumab or placebo. Patients were randomized using a permuted block method at baseline. Central randomization occurred using an interactive web-based response system. Performance bias: blinding of participants and personnel. Assessment made for class of outcomes. Patient-reported outcomes: PASI, DLQI Objective outcomes: Adverse events, Withdrawal irrespective of reason Low Low To maintain the blind, both guselkumab and adalimumab placebos were administered as necessary. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) (ClinicalTrials.gov). Ibid. Detection bias: blinding of outcome assessment. Assessment made for class of outcomes. Patient-reported outcomes: PASI, DLQI Objective outcomes Adverse events, Withdrawal irrespective of reason Attrition bias: incomplete outcome data. Assessment made for class of outcomes. Low Low Unclear Adequate blinding. Nothing suggests that masking/blinding was unveiled during the study. Ibid. All randomized patients were included in the primary analysis and some secondary efficacy analyses according to their assigned treatment group. Safety analyses included all patients receiving at least 1 study agent administration ( 1 dose of guselkumab). Patients who discontinued treatment due to lack of efficacy or an adverse event [AE] of worsening of psoriasis, or started a protocol-prohibited medication/therapy to improve psoriasis were considered treatment failures. Patients meeting treatment failure criteria before week 16 and patients not returning for week-16 evaluation were considered nonresponders for the week- 16 primary end points. Statistical handling of missing data/nonresponders is not clarified. When assessing DLQI response, the percentage of participants who achieved a DLQI score = 0 or 1 was analyzed for patients with baseline DLQI > 1 only (n = 491 for guselkumab; n = 246 at week 16), as specified in the study protocol (Clinical Trials.gov). We consider this to be a deviation from good clinical practice, however, as only a few patients were excluded from these analyses (0.8-1 %), we do not consider this to have substantially affected the results. Side 28 af 33

60 Reporting bias: selective reporting outcome data. Low Nothing suggests reporting bias due to selective outcome reporting, cf. clinicaltrials.gov. Other bias Low No other concern regarding potential risk of bias. Overall bias Low Overall risk of bias judged low. Side 29 af 33

61 GRADE-evaluering af evidenskvaliteten til vurdering af den kliniske merværdi af tildrakizumab Hvad er den kliniske merværdi af tildrakizumab til voksne patienter med moderat til svær plaque psoriasis, som er kandidater til 2. generations immunmodulerende behandling og ikke har psoriasisartropati? GRADE evidensprofil, tildrakizumab vs. placebo Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations tildrakizumab placebo Relative (95% CI) Absolute (95% CI) Certainty Importance PASI75 2 randomised trials not serious not serious not serious not serious none 445/616 (72.2%) 18/311 (5.8%) RR (7.69 to 20.00) 666 more per (from 387 more to more) HIGH CRITICAL PASI90 2 randomised trials not serious not serious not serious not serious none 308/616 (50.0%) 6/311 (1.9%) RR (11.11 to 50.00) 463 more per (from 195 more to 945 more) HIGH IMPORTANT DLQI Side 30 af 33

62 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations tildrakizumab placebo Relative (95% CI) Absolute (95% CI) Certainty Importance 2 randomised trials not serious not serious not serious not serious none 309/616 (50.2%) 20/311 (6.4%) RR 7.69 (5.00 to 12.50) 430 more per (from 257 more to 740 more) HIGH IMPORTANT Alvorlige uønskede hændelser 2 randomised trials not serious not serious not serious serious a none 24/616 (3.9%) 5/311 (1.6%) RR 2.17 (0.82 to 5.88) 19 more per (from 3 fewer to 78 more) MODERATE CRITICAL Behandlingsophør 2 randomised trials not serious serious b not serious serious a none 59/616 (9.6%) 23/311 (7.4%) RR 1.22 (0.36 to 4.17) 16 more per (from 47 fewer to 234 more) LOW IMPORTANT CI: Confidence interval; RR: Risk ratio Explanations a. Konfidensintervallet inkluderer både negativ og positiv merværdi. b. Heterogeniteten i metanalysen var høj (I 2 = 84,5 %). Side 31 af 33

63 GRADE evidensprofil, guselkumab vs. placebo Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations guselkumab placebo Relative (95% CI) Absolute (95% CI) Certainty Importance PASI75 2 randomised trials not serious not serious not serious not serious none 742/825 (89.9%) 30/422 (7.1%) RR (9.09 to 16.67) 818 more per (from 575 more to more) HIGH CRITICAL PASI90 2 randomised trials not serious not serious not serious not serious none 637/825 (77.2%) 11/422 (2.6%) RR (16.67 to 50.00) 843 more per (from 408 more to more) HIGH IMPORTANT DLQI 2 randomised trials not serious not serious not serious not serious none 478/825 (57.9%) 15/422 (3.6%) RR (10.00 to 50.00) 557 more per (from 320 more to more) HIGH IMPORTANT Side 32 af 33

64 Certainty assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations guselkumab placebo Relative (95% CI) Absolute (95% CI) Certainty Importance Alvorlige uønskede hændelser 2 randomised trials not serious not serious not serious serious a none 18/496 (3.6%) 3/248 (1.2%) RR 3.03 (0.89 to 10.00) 25 more per (from 1 fewer to 109 more) MODERATE CRITICAL Behandlingsophør 2 randomised trials not serious not serious not serious serious a none 26/496 (5.2%) 15/248 (6.0%) RR 1.19 (0.74 to 1.96) 11 more per (from 16 fewer to 58 more) MODERATE IMPORTANT CI: Confidence interval; RR: Risk ratio Explanations a. Konfidensintervallet indeholder både negativ og positiv merværdi. Side 33 af 33

65 Application for the assessment of clinically added value of Ilumetri for treatment of moderate to severe plaque psoriasis Version Version log Original application Friday December 14, 2018 The Medicines Council requested an update: -RR estimates inverted and ARR added for all outcomes -Appendix F added showing results of the indirect analysis of DLQI 0/1 responder rate based on alternative definition of population

66 Contents 1 Basic information Abbreviations Summary Literature search... 7 Relevant studies... 7 Main characteristics of included studies Clinical questions What is the clinical added value of tildrakizumab in adult patients with moderate to severe plaque psoriasis, who are candidates for second generation immunomodulating treatment and who do not have psoriasis arthropathy? Presentation of relevant studies Results per study Comparative analyses Subgroup analysis of Ilumetri trials Other considerations Possibility to pause treatment Possibility of dose reduction of dose interval prolongation Elaboration on possibility to use 200 mg for patients with certain characteristics Relationship between loading dose and maintenance dose Maintenance of response between dosing every 12 weeks References APPENDIX A: Literature search Search strategy Study Selection Full text publication excluded APPENDIX B: Forest Plots, Week analysis APPENDIX C: Indirect comparison Week Forest Plots, Week Assessment of Heterogeneity Risk ratios APPENDIX D: Indirect comparison week Sensitivity analysis Forest Plots, Week 12-16, sensitivity analysis Assessment of Heterogeneity Version Page 2 of 79

67 3 Risk ratios APPENDIX E: DLQI sensitivity analysis. Change from baseline Week meta-analyses and indirect comparison Week meta-analyses and indirect comparison APPENDIX F: DLQI sensitivity analysis. Population of analysis Basic information TABLE 1 CONTACT INFORMATION Name Mette Lange Title Market Access Manager Area of responsibility Market Access Phone Mette.lange@almirall.com Name Kristian Garn Du Jardin Title Medical Science Liaison Area of responsibility Medical Phone kristian.dujardin@almirall.com TABLE 2 OVERVIEW OF THE PHARMACEUTICAL Proprietary name Generic name Marketing authorization holder in Denmark ATC code Pharmacotherapeutic group Active substance(s) Pharmaceutical form(s) Mechanism of action Ilumetri Tildrakizumab Almirall, S.A. Ronda General Mitre, Barcelona Spanien L04AC17 Immunosuppressants, interleukin inhibitors Each pre-filled syringe contains 100 mg of tildrakizumab in 1 ml. Ilumetri 100 mg solution for injection in pre-filled syringe Tildrakizumab is a humanized IgG1/k monoclonal antibody that specifically binds to the p19 protein subunit of the interleukin-23 (IL-23) cytokine without binding to IL- 12 and inhibits its interaction with the IL-23 receptor. Version Page 3 of 79

68 IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines. Dosage regimen The recommended dose of Ilumetri is 100 mg by subcutaneous injection at week 0, and 4 and every 12 th week thereafter. In patients with certain characteristics (e.g. high disease burden, body weight 90 kg) 200 mg may provide greater efficacy Therapeutic indication relevant for assessment (as defined by the European Medicines Agency, EMA) Other approved therapeutic indications Will dispensing be restricted to hospitals? Combination therapy and/or co-medication Packaging types, sizes/number of units, and concentrations Orphan drug designation Consideration should be given to discontinuing treatment in patients who have shown no response after 28 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 28 weeks. Ilumetri is indicated for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Not applicable Yes Not applicable 100 mg pre-filled syringe. Pack of 1 Not applicable 2 Abbreviations ADA Adalimumab AE Adverse Event ARR Absolute risk reduction BIW Twice a week BMI Body mass index BSA Body surface area CASPAR Classification Criteria for Psoriatic Arthritis CI Confidence interval DLQI Dermatology Life Quality Index FE Fixed effects Gus Guselkumab IGA Investigators global assessment IL Interleukin Inf Infinite ITC Indirect treatment comparison ITT Intention-to-treat IV Intravenous Version Page 4 of 79

69 kg NA NAPSI NR NRI p.p. PASI PBO PGA PR PsA PSSD Q12W Q8W qow R RE RE s.c. SAE SD TNF-a USA Kilogram Not applicable / Not available Nail psoriasis severity index Non-responders/ not reported Non-responder imputation Percentage points Psoriasis Area Sensitivity Index Placebo Physicians global assessment Partial responders Psoriatic arthritis. Psoriasis signs and symptoms diary Every 12 weeks Every 8 weeks Every other week Responders Responders Random effects Subcutaneous Serious Adverse Event Standard deviation Tumor necrosis factor-alpha United States of America Version Page 5 of 79

70 3 Summary Introduction: This application serves as the basis for the assessment of added clinical value of tildrakizumab (Ilumetri ) for adult patients with moderate to severe plaque psoriasis (without psoriasis arthropathy), who are candidates for second generation immunomodulating therapy. The application form at hand focuses on the clinical aspects of tildrakizumab, and is supported by a separate health economic analysis. Tildrakizumab is a humanized IgG1/k monoclonal antibody with high affinity for the p19 of interleukin (IL) 23 [1]. By binding to IL-23, tildrakizumab blocks the interaction between this cytokine and the IL-23 receptor [1]. Recent evidence has established a pivotal role of the T-helper cell 17 inflammation pathway in psoriasis, and by blocking IL-23, tildrakizumab provides upstream inhibition of this cascade [2]. A European marketing authorization for Ilumetri was granted by the European Commission on 17 th of September, Method: Almirall chose guselkumab (Tremfya) as comparator for this application because the two products have identical mechanism of action, almost similar dosing regimen as well as comparable time period for clinical development. The literature search identified five relevant phase III trials (including one trial in a Japanese population) that evaluated the safety and efficacy of either tildrakizumab 100 mg Q12W or guselkumab 100 mg Q8W. A Bucher indirect comparison was undertaken using placebo as common comparator at week and week The Japanese study was only included in a sensitivity analysis since it was deemed incomparable to the other trials due to differences in baseline characteristics. The treatments were narratively compared at ~1 year of therapy. Finally, a subgroup PASI 90 analysis based on previous treatment experience was conducted. Results: At week 24-28, the analysis did not reveal any statistically significant difference between guselkumab and tildrakizumab for PASI 75, PASI 90, SAE and rate of discontinuations. For DLQI 0/1 the risk ratio was statistically significant in favor of guselkumab, however the clinical relevance of this finding is uncertain. A sensitivity analysis of the comparative treatment effects on DLQI was performed comparing DLQI change from baseline as the outcome measure. This analysis showed no statistically significant differences in treatment effect on patient quality of life. The week analysis as well as further sensitivity analysis yielded identical findings. The PASI 90 response to tildrakizumab was equal between patients with previous exposure to biologics and biologic naïve patients. No data exists for patients who have previously failed on a biologic including treatments that target IL-23. Comparison beyond week 28 was obscured by major differences in trial design. However, the two treatments appeared to display similar high maintenance of response throughout ~1 year of therapy, and the risk of serious adverse events was very low and equal for both treatments over this time period. Conclusion: For all critical endpoints (PASI 75 and SAEs) as well as all but one important endpoint, no difference was detected between tildrakizumab and guselkumab. Findings in favour of guselkumab in terms of DLQI responders were not supported in sensitivity analyses using change in DLQI scores as treatment effect, thereby questioning the clinical relevance of the former result. Long term efficacy and safety also appeared equal between the two treatments. These strong clinical evidence as well as convenient dosing regimen position tildrakizumab as an ideal first-line treatment option for adult psoriasis patients, who are candidates for second generation immunomodulating therapy. Finally, Almirall has addressed a number of relevant questions posed by the Medical Council pertaining to the clinical use of tildrakizumab in a Danish setting using all relevant published and unpublished data. Version Page 6 of 79

71 4 Literature search Databases and search strategy In the protocol from the Expert Committee for psoriasis, Almirall was given the freedom to choose a comparator for this assessment among the group of current first-line 2 nd generation immunomodulatory therapies. Due the identical mechanism of action, similar dosing regimen as well as comparable time period for clinical development, Almirall chose guselkumab (Tremfya) as comparator. Searches were undertaken on the 20 th November Details on the search terms and selection process is available in Appendix A. 95 records were retrieved from MEDLINE and 89 records from CENTRAL. Following de-duplication, 154 unique records were assessed for relevance. Records where scanned to identify phase III, randomized controlled trials reporting on outcomes of relevance to the scientific questions using guselkumab as the comparator. Details on the eligibility criteria applied is available in Appendix A. A PRISMA study flow diagram (Appendix A, Figure A.2) shows the number of records identified by the search and the numbers excluded at various selection stages. Full texts of potentially relevant studies were obtained and assessed in detail for relevance to the review s eligibility criteria. This produced a list of eligible and ineligible studies. Where results for one study were reported in more than one paper, all related papers were identified and grouped together to ensure that participants in individual studies were only included once. Documents excluded following full-text review are listed in Appendix A (table A.3) along with the reason for exclusion. Relevant studies Five studies (reported in ten documents) met the eligibility criteria for the systematic review and indirect treatment comparison: 2 trials of tildrakizumab (Re-SURFACE 1 and 2 [3]) 3 trials of guselkumab (VOYAGE 1 and 2 [4, 5], and Ohtsuki 2018 [6]) The Ohtsuki trial only included Japanese patients and will only be considered in the sensitivity analysis (appendix D). The rationale to exclude the Japanese trial from the main analysis is given in TABLE 4.1: RELEVANT STUDIES INCLUDED IN THE ASSESSMENT References (title, author, journal, year) Trial name NCT number Dates of study Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (resurface 1 and resurface 2): results from two randomised controlled, phase 3 trials Reich K, Papp KA, Blauvelt A, Tyring SK, Sinclair R, Thaci D, et al. resurface 1 NCT Start: completion: Est. completion: Lancet. 2017;390(10091):276-88*. resurface 2 NCT Start: completion: Est. completion: Efficacy and safety of guselkumab, an antiinterleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment VOYAGE 1 NCT Start completion: Version Page 7 of 79

72 References (title, author, journal, year) Trial name NCT number Dates of study of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. Blauvelt A, Papp KA, Griffiths CEM, Randazzo B, Wasfi Y, Shen Y-K, et al. J Am Acad Dermatol. 2017;76(3): Est. completion: Long-Term Efficacy of Guselkumab for the Treatment of Moderate-to-Severe Psoriasis: Results from the phase 3 VOYAGE 1 Trial Through Two Years. Griffiths CEM, Papp KA, Kimball AB, Randazzo B, Song M, Li S, et al. J Drugs Dermatol. 2018;17(8): Patient-reported symptoms and signs of moderate-to-severe psoriasis treated with guselkumab or adalimumab: results from the randomized VOYAGE 1 trial. Papp KA, Blauvelt A, Kimball AB, Han C, Randazzo B, Wasfi Y, et al. J Eur Acad Dermatol Venereol. 2018;32(9): Efficacy of Guselkumab Compared With Adalimumab and Placebo for Psoriasis in Specific Body Regions: A Secondary Analysis of 2 Randomized Clinical Trials. Foley P, Gordon K, Griffiths CEM, Wasfi Y, Randazzo B, Song M, et al. JAMA Dermatol. 2018;154(6): Efficacy of guselkumab in subpopulations of patients with moderate-to-severe plaque psoriasis: a pooled analysis of the phase III VOYAGE 1 and VOYAGE 2 studies. Gordon KB, Blauvelt A, Foley P, Song M, Wasfi Y, Randazzo B, et al. Br J Dermatol. 2018;178(1): Improvement in Patient-Reported Outcomes (Dermatology Life Quality Index and the Psoriasis Symptoms and Signs Diary) with Guselkumab in Moderate-to-Severe Plaque Psoriasis: Results from the phase III VOYAGE 1 and VOYAGE 2 Studies. Armstrong AW, Reich K, Foley P, Han C, Song M, Shen Y-K, et al. Am J Clin Dermatol. 2018;12:12. Efficacy and safety of guselkumab, an antiinterleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. Reich K, Armstrong AW, Foley VOYAGE 2 NCT Start: completion: Est. completion: Version Page 8 of 79

73 References (title, author, journal, year) Trial name NCT number Dates of study P, Song M, Wasfi Y, Randazzo B, et al. J Am Acad Dermatol. 2017;76(3): Anxiety and depression in patients with moderate-to-severe psoriasis and comparison of change from baseline after treatment with guselkumab vs. adalimumab: results from the Phase 3 VOYAGE 2 study. Gordon KB, Armstrong AW, Han C, Foley P, Song M, Wasfi Y, et al. J Eur Acad Dermatol Venereol. 2018;32(11): Efficacy of Guselkumab Compared With Adalimumab and Placebo for Psoriasis in Specific Body Regions: A Secondary Analysis of 2 Randomized Clinical Trials. Foley P, Gordon K, Griffiths CEM, Wasfi Y, Randazzo B, Song M, et al. JAMA Dermatol. 2018;154(6): Efficacy of guselkumab in subpopulations of patients with moderate-to-severe plaque psoriasis: a pooled analysis of the phase III VOYAGE 1 and VOYAGE 2 studies. Gordon KB, Blauvelt A, Foley P, Song M, Wasfi Y, Randazzo B, et al. Br J Dermatol. 2018;178(1): Improvement in Patient-Reported Outcomes (Dermatology Life Quality Index and the Psoriasis Symptoms and Signs Diary) with Guselkumab in Moderate-to-Severe Plaque Psoriasis: Results from the phase III VOYAGE 1 and VOYAGE 2 Studies. Armstrong AW, Reich K, Foley P, Han C, Song M, Shen Y-K, et al. Am J Clin Dermatol. 2018;12:12. Guselkumab, an anti-interleukin-23 monoclonal antibody, for the treatment of moderate to severe plaque-type psoriasis in Japanese patients: Efficacy and safety results from a phase 3, randomized, double-blind, placebocontrolled study. Ohtsuki M, Kubo H, Morishima H, Goto R, Zheng R, Nakagawa H. J Dermatol. 2018;45(9): *.Erratum appears in Lancet Jul 15;390(10091):230 Main characteristics of included studies Characteristics of included studies are presented in section Ohtsuki 2018 NCT Start: completion: Est. completion: Version Page 9 of 79

74 5 Clinical questions What is the clinical added value of tildrakizumab in adult patients with moderate to severe plaque psoriasis, who are candidates for second generation immunomodulating treatment and who do not have psoriasis arthropathy? Presentation of relevant studies The study designs, methods, outcomes, patient populations are summarised in Table 5.1 to Table 5.3. resurface 1 and resurface 2 resurface 1 was a 64-week, phase III, randomized, placebo-controlled, parallel design study to evaluate the efficacy and safety/tolerability of subcutaneous (s.c.) tildrakizumab, followed by an optional Long-Term Safety Extension Study, in patients with moderate-to-severe chronic plaque psoriasis. The study consisted of a 4-week screening period, a 12-week Part 1 period (Week 0 to Week 12), a 16-week Part 2 period (Week 12 to Week 28), a 36-week Part 3 period (Week 28 to Week 64), an optional 4 year long term extension, and a 20-week follow-up period (Figure 5.1). FIGURE 5.1 RESURFACE 1 DESIGN Non-responders (NR: who achieved <50% improvement in PASI response from baseline) were discontinued at Week 28. Partial responders (PR) were subjects who achieved 50% but <75% improvement in PASI response from baseline. Responders (R) were subjects who achieved 75% improvement in PASI response from baseline. * Participants in the placebo group (Arm C) were rerandomized (1:1) at Week 12 to receive either tildrakizumab 200 mg or 100 mg; participants in the tildrakizumab 100 mg and 200 mg groups were re-randomized at Week 28 depending on whether they had a response or partial response to treatment. ** Participants in Arms A and B who relapsed on placebo between Week 28 and Week 64 were re-initiated on their initial treatment with tildrakizumab (100 mg or 200 mg). Adapted from Reich et al 2017, supplementary appendix. [3] resurface 2 was a phase III, randomized, double-blind, active-comparator and placebo-controlled, parallel-group trial to evaluate the efficacy and safety/tolerability of tildrakizumab s.c., followed by an optional long-term safety extension study, in patients with moderate-to-severe chronic plaque psoriasis. Version Page 10 of 79

75 FIGURE 5.2 RESURFACE 2 DESIGN NRs were subjects who achieved <50% improvement in PASI response from baseline. PR were subjects who achieved 50% but <75% improvement in PASI response from baseline. R were subjects who achieved 75% improvement in PASI response from baseline. In Arms A and B, NRs were discontinued at Week 28, whereas in Arm D, Rs were discontinued at Week 28 *Participants in the placebo group (Arm C) were re-randomized (1:1) at Week 12 to receive either tildrakizumab 200 mg or 100 mg; participants in the tildrakizumab 200 mg group (Arm A) and 100 mg group (Arm B) were re-randomized at Week 28 depending on whether they had a response or partial response to treatment. In Arm D, there was a 4-week washout period in NR and PR patients on etanercept before they started tildrakizumab 200 mg. Abbreviations: NR: non-responders; R: responders. Adapted from Reich et al 2017, supplementary appendix [3] Table 5.2 shows the list of primary, secondary endpoints and planned subgroup analyses. The co-primary endpoints in both resurface 1 and resurface were proportions of patients with PASI 75 response and PGA score of clear or minimal, with at least a 2 grade reduction from baseline at Week 12. The secondary endpoints included PASI 75, 90, 100 and PGA at different time points as well as patient reported outcomes e.g. DLQI at different timepoints. One of the key secondary endpoints in resurface 2 was to assess the efficacy of tildrakizumab compared to etanercept. Table 5.1 lists the inclusion and exclusion criteria for the trials and Table 5.3 shows the baseline characteristics of patients included in the two trials. Baseline DLQI score appear equal to Danish patients initiating second-generation immunomodulatory anti-psoriasis treatment[7], whereas the initial PASI score seems similar to recent phase III trials for other biologics[5, 8]. Of note, 23 % of participants had previously attempted biological treatment in resurface 1, and % in resurface 2. Consort diagrams for both trials can be found in [3]. VOYAGE 1 and VOYAGE 2 VOYAGE 1 and VOYAGE 2 are placebo- and active-comparator controlled studies with identical study designs through Week 24, to assess the efficacy, safety, pharmacokinetics, and immunogenicity of guselkumab in subjects with moderate to severe plaque psoriasis who are candidate for phototherapy or systemic therapy (Figure 5.3 and Figure 5.4). The designs diverge beyond Week 24, with each study addressing a distinct aspect of psoriasis treatment between Week 24 and 48. In the VOAYGE 1 study, treatment of subjects randomized to guselkumab and adalimumab continued through Week 48 to allow for an evaluation of the durability of response and comparative efficacy and safety during one year of Version Page 11 of 79

76 continuous treatment. VOYAGE 2 incorporated randomized withdrawal and retreatment design elements from Week 28 and beyond, to assess the efficacy and safety of guselkumab maintenance dosing relative to withdrawal of treatment in PASI 90 responders. VOYAGE 2 also provides efficacy and safety information on adalimumab PASI 90 non-responders who transitioned to guselkumab treatment at Week 28. FIGURE 5.3 VOYAGE 1 DESIGN Abbreviations: ADA: adalimumab; Gus: Guselkumab; PBO: Placebo; Q8W: every 8 weeks; qow: every other week. Source: Medicinrådets Anbefalingsrapport Guselkumab Psoriasis [9] Version Page 12 of 79

77 FIGURE 5.4 VOYAGE 2 DESIGN Abbreviations: ADA: adalimumab; Gus: Guselkumab; PBO: Placebo; NR: non-responders; Re: responders Q8W: every 8 weeks; qow: every other week. Source: Medicinrådets Anbefalingsrapport Guselkumab Psoriasis [9] Table 5.2 shows the list of primary and secondary endpoints. The co-primary endpoints in both VOYAGE 1 and VOYAGE 2 were proportion of subjects who achieved IGA 0/1 and proportion of subjects who achieved PASI 90 response at Week 16. The secondary endpoints included PASI 75, 90, 100 and IGA at different time points as well as patient reported outcomes e.g. change of DLQI from baseline to week 16. Table 5.1 lists the inclusion and exclusion criteria for the trials and Table 5.3 shows the baseline characteristics of patients included in the two trials. Consort diagrams for both trials can be found in the primary publications [4, 5]. Ohtsuki 2018 Ohtsuki 2018 is a 52-week, phase III, randomized, double-blind, placebo-controlled study with the primary objective to evaluate efficacy and safety of guselkumab in Japanese patients with moderate to severe plaque psoriasis. The study comprised a placebo-controlled period (week 0 16), a placebo cross-over and active treatment period (week 16 52) and a long-term extension phase (see study design illustration in the primary publication [6]). Eligible patients were randomized (1:1:1) to guselkumab 50 mg, 100 mg or placebo, with injections (s.c.) at week 0, 4, and every 8 weeks (Q8W) thereafter. Patients receiving placebo were crossed over to receive (1:1) guselkumab 50 mg or 100 mg at week 16 and 20 and every Q8W thereafter. Version Page 13 of 79

78 The co-primary end-points were the proportion of patients achieving an IGA cleared/minimal (0/1) and PASI-90 response ( 90% improvement in PASI from baseline) at week 16. The key secondary end-points included the proportion of patients who achieved a PASI-75 response ( 75% improvement in PASI from baseline) and change from baseline in DLQI score at week 16. Other secondary end-points evaluated at week 16 and through week 52 include proportion of patients with IGA 0, IGA 0/1, PASI-50, PASI-75, PASI-90 ( 90% improvement) and PASI-100 (100% improvement); proportion of patients who achieved a DLQI score of 0 or 1 (among patients with a baseline DLQI score of >1); and proportion of patients who achieved a reduction of 5 or more in the DLQI score from baseline (Table 5.2). No data was captured specifically at week to enable inclusion of this trial in the indirect comparison at this time horizon, but the week 16 results was included in week 16 indirect comparison as a sensitivity analysis. Table 5.1 lists the inclusion and exclusion criteria for the trials and Table 5.3 shows the baseline characteristics of patients included in the trial. Although not explicitly stated, the study had an entirely Japanese patient population. The consort diagram of the trial is available in the primary publication [6]. Comparability of populations The trials were broadly similar in terms of patient characteristics. However, we note that, while four of the trials were in predominantly white or Caucasian populations, the Ohtsuki et al trial had an entirely Japanese patient population. The gene pool is naturally different between Japanese and Caucasian patients, which could lead to different metabolism of medicines and response to therapy. Furthermore, the patient baseline characteristics of the Ohtsuki 2018 trial is not comparable with neither the VOYAGE trials nor the resurface trials (see 5.1.1). Importantly, the PASI score as well as body surface area (BSA) involvement are considerably higher in the Japanese patients (PASI ~26 and BSA ~37 versus PASI ~21 and BSA ~29) compared to the participants of the four main trials, whereas the DLQI score is somewhat lower (~10 versus ~14). Finally, the mean body weight approximate 72 kg in the Japanese participants whereas it is ~ 89 kg for the mainly Caucasian patient population. For these reasons the Ohtsuki 2018 trial was only included in a sensitivity analysis. Version Page 14 of 79

79 TABLE 5.1: SUMMARY OF HYPOTHESES, POPULATIONS AND ELIGIBILITY CRITERIA Trial name Hypothesis objective Population Inclusion criteria Exclusion criteria resurface 1 [3] To assess the efficacy, safety and tolerability of tildrakizumab compared with placebo. Adults with moderate to severe chronic plaque psoriasis Men and women aged 18 years; Moderate-to-severe chronic plaque psoriasis (BSA involvement 10%, PGA score 3, and PASI score 12); Candidates for phototherapy or systemic therapy. Women of child-bearing potential had to practise abstinence or use medically accepted contraception methods. Active or untreated latent tuberculosis Infection requiring antibiotic treatment within 2 weeks of screening Severe infection requiring hospitalization or IV antibiotics within 8 weeks of study Live viral or bacterial vaccination within 4 weeks of the study; Positive test for HIV, hepatitis B virus infection, or hepatitis C virus infection; Previous malignancy (except for successfully treated basal cell carcinoma, squamous cell carcinoma of the skin in situ, squamous cell carcinoma with no evidence of recurrence within 5 years, or adequately treated carcinoma in situ of the cervix); Hospital admission for an acute cardiovascular event, illness, or surgery within 6 months of the trials; Uncontrolled hypertension Uncontrolled diabetes; and previous use of tildrakizumab or other interleukin 23 and 17 pathway inhibitors (p40,p19, and interleukin 17 antagonists); Pregnancy. Further extensive inclusion criteria were provided in the supplementary appendix, most notably: Non-plaque forms of psoriasis specifically erythrodermic psoriasis, predominantly pustular psoriasis, medication-induced or medicationexacerbated psoriasis, or new onset guttate psoriasis. Version Page 15 of 79

80 Trial name Hypothesis objective Population Inclusion criteria Exclusion criteria resurface 2 [3] VOYAGE 1 [4] VOYAGE 2 [5] To assess the efficacy, safety and tolerability of tildrakizumab compared with placebo and etanercept. To compare efficacy and safety of guselkumab with adalimumab and placebo in patients with psoriasis treated for 1 year. To evaluate the efficacy, safety, and tolerability of guselkumab to treat patients with moderate to severe plaque-type psoriasis. Adults with moderate to severe chronic plaque psoriasis Adults with moderate to severe psoriasis Adults with moderate to severe psoriasis Same as resurface 1 Same as resurface 1 Age 18 years Moderate to severe plaque psoriasis (Investigator global assessment 3, PASI 12, body surface area 10%) for at least 6 months Candidates for systemic or phototherapy. Age years Moderate to severe plaque psoriasis (Investigator global assessment 3, PASI 12, body surface area 10%) for at least 6 months Candidates for systemic or phototherapy. History or current signs of a severe, progressive, or uncontrolled medical condition or had current or history of malignancy (except non-melanoma skin cancer), within 5 years History or symptoms of active tuberculosis Had received guselkumab or adalimumab, other anti TNF alpha therapy (within 3 months), other treatment targeting IL-12/23, IL-17, or IL-23 (6 months) or any systemic immunosuppressants (e.g., methotrexate) or phototherapy (4 weeks). Non-plaque forms of psoriasis (for example, erythrodermic, guttate, or pustular) Current drug-induced psoriasis (for example, a new onset of psoriasis or an exacerbation of psoriasis from beta blockers, calcium channel blockers, or lithium) Prior use of guselkumab or adalimumab History or current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances Pregnant, nursing, or planning a pregnancy (both men and women) within 5 months following the last administration of study drug Any condition that, in the opinion of the investigator, would make participation not be in the best interest (for example, compromise the well-being) of the participant or that could Version Page 16 of 79

81 Trial name Hypothesis objective Population Inclusion criteria Exclusion criteria Ohtsuki 2018 [6] To evaluate efficacy and safety of guselkumab in Japanese patients with moderate to severe plaquetype psoriasis. Japanese adults with moderate to severe psoriasis 20 years of age Moderate to severe plaque-type psoriasis 6 months or more at PASI 12 IGA 3 BSA 10% at baseline Candidates for phototherapy or systemic treatment for psoriasis or Diagnosis of psoriatic arthritis (PsA) using CASPAR, and with active PsA (defined as 3 swollen joints and 3 tender joints at baseline and C-reactive protein of 0.3 mg/dl or more at baseline) prevent, limit, or confound the protocol-specified assessments Non-plaque-type psoriasis Drug induced psoriasis Latent or active tuberculosis Chronic or recurrent infectious disease Malignancy within 5 years (except nonmelanoma skin cancer or cervical carcinoma that had been treated, and with no evidence of recurrence within 3 months) Anaphylactic reactions History or current signs or symptoms of any severe, progressive or uncontrolled medical disorders Prior treatment with: - Guselkumab or anti-tnf-a agents within 3 months or five halflives, (whichever was longer) - Biological therapy targeting IL-12, IL-17 or IL-23 within 6 months - Systemic immunosuppressants (e.g. methotrexate, cyclosporin) within 4 weeks - Phototherapy within 4 weeks of enrolment BSA- body surface area; IV- intravenous; PASI- Psoriasis Area Sensitivity Index; PGA- physicians global assessment; PsA - psoriatic arthritis. Version Page 17 of 79

82 TABLE 5.2: SUMMARY OF OUTCOMES, ANALYSIS AND DATA MANAGEMENT Trial identifier resurface 1 [3] Primary and secondary outcomes Primary outcomes: Proportion of participants achieving at least 75% improvement in PASI (PASI 75) and the proportion of participants achieving a PGA score of clear or minimal, with at least a two-grade reduction from baseline, at week 12. Secondary outcomes: PASI 90 and PASI 100 at week 12, DLQI (proportion of patients with a score of 0 or 1) at week 12 and 28, and PASI 75 in tildrakizumab patients receiving continuous treatment from baseline to the end of week 64. Randomisation and blinding Participants were randomly assigned (2:2:1) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo, then in part 2, those in the placebo group were rerandomised (1:1) to either tildrakizumab 200 or 100 mg. Randomisation was done via computer generated randomisation sequences, and an interactive voice-response system / web-response system. Randomization was done by region. Patients were stratified by bodyweight ( 90 kg or >90 kg) and previous exposure to biologics therapy for psoriasis, and in Japan also for psoriatic arthritis at baseline. The study was double-blind (Investigators, participants, and study personnel) until completion of the studies. Tildrakizumab and its matching placebo or etanercept and its matching placebo were identical in appearance and packaging. Additional placebo doses were administered to maintain masking. Subgroup analyses planned Bodyweight ( 90 kg or >90 kg); Previous exposure to biologics. Results were also reported by the following: Age (<65, 65) Gender Race Region TNF antagonist response among subjects previously treated for psoriasis (Yes/No) Psoriatic Arthritis (Yes/No) Statistical analysis Co-primary endpoints were analysed using the Cochran-Mantel- Haenszel test; p- values were not adjusted for multiplicity. Percentage differences and 95% CIs were calculated with the Miettinen- Nurminen method with sample size weights; % differences shown are absolute differences. Data management: - details of patient withdrawals - missing data imputation Number participants completed/entered stage (reasons for discontinuation; total) Part I (In order: lack of efficacy; adverse effects; lost to follow-up; protocol violation; participant withdrawal): Tildrakizumab 200 mg: 298/308 (NR; 5; 1; 1; 2; 1 pregnancy; total 10) Tildrakizumab 100 mg: 300/309 (1; NR; 2; NR; 3; 3 physician decision; total 9) Placebo: 146/155 (2; NR; 1; 1; 3; also 1 physician decision and 1 progressive disease; total 9) Part 2 (In order: adverse effects; lack of efficacy; lost to follow-up; drug noncompliance; protocol violation; patient withdrawal): Tildrakizumab 200 mg: 279/298 (3; 3; NR; 1; 1; 5; 6 other; total 19) Tildrakizumab 100 mg: 268/299 (NR; 11; 3; 1; NR; 3; 10 other; 2 physician decision; 1 progressive disease; total 31) Placebo- Tildrakizumab 200 mg: 62/72 (1; 3; 1; NR; NR; 2; 2 other; 1 pregnancy; total 10) Placebo- Tildrakizumab 100 mg: 67/74 (NR; 3; 1; NR; NR; 2; 1 other; total 7) Non-responder imputation was prespecified and was shown for all data, except for DLQI, which were observed data. Version Page 18 of 79

83 Trial identifier resurface 2 [3] Primary and secondary outcomes Primary outcomes: Proportion of participants achieving at least 75% improvement in PASI (PASI 75) and the proportion of participants achieving a PGA score of clear or minimal, with at least a two-grade reduction from baseline, at week 12. Secondary outcomes: PASI 90 and PASI 100 at week 12, PASI75 and PGA response at Week 28, DLQI (proportion of patients with a score of 0 or 1) at week 12 and 28, and PASI 75 in tildrakizumab patients receiving continuous treatment from baseline to the end of week 52. Randomisation and blinding Participants were randomly assigned (2:2:1:2) to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg. In part 2, the placebo group was rerandomised (1:1) to tildrakizumab 200 mg or 100 mg. In part 3 of both studies, responders (PASI 75) and partial responders (PASI 50 and PASI <75) to tildrakizumab 200 mg and 100 mg were rerandomized at 28 weeks to continue the same treatment, a different dose of tildrakizumab, or placebo. Randomisation was done as in resurface 1. Patients was stratified by bodyweight ( 90 kg or >90 kg), previous exposure to biologics therapy for psoriasis, non-response to at least one traditional systemic medication, and in Japan also for psoriatic arthritis at baseline. Blinding was done as in resurface 1 Subgroup analyses planned Same as resurface 1 Statistical analysis Co-primary endpoints were analysed using the Cochran-Mantel- Haenszel test; p- values and a stepdown multiplicity strategy was used. Percentage differences and 95% CIs were calculated with the Miettinen- Nurminen method with sample size weights; % differences shown are absolute differences. Descriptive summary statistics by treatment were reported for participants rerandomised from placebo to tildrakizumab 100 mg or 200 mg. Data management: - details of patient withdrawals - missing data imputation Number participants completed/entered stage (reasons for discontinuation; total) Part I (In order: AE; lack of efficacy; lost to follow-up; protocol violation; participant withdrawal): Tildrakizumab 200 mg: 300/314 (2; 1; 1; 2; 5; 2 other; 1 drug non-compliance; total 14) Tildrakizumab 100 mg: 295/307 (1; NR; 2; 1; 7; 1 pregnancy; total 12) Etanercept: 289/313 (5; NR; 3; NR; 6; 4 other; 4 physician decision; 1 pregnancy ; 1 progressive disease; total 24) Placebo: 142/156 (2; 2; 3; 1; 5; 1 other; total 14) Part 2 (In order: AE; lack of efficacy; lost to follow-up; patient withdrawal): Tildrakizumab 200 mg: 294/300 (2; NR; NR; 3; 1 other; total 6) Tildrakizumab 100 mg: 289/294 (NR; NR; 2; 2; 1 pregnancy; total 5) Etanercept: 277/289 (2; 2; 2; 4; 1 drug non-compliance; 1 pregnancy; total 12) Placebo- Tildrakizumab 200 mg: 69/72 (NR; NR; 1; 1; 1 other; total 3) Placebo- Tildrakizumab 100 mg: 66/70 (1; 2; NR; 1; total 4) VOYAGE 1 [4] Primary outcomes: Patients were randomized using a NR Coprimary outcomes Over the 48 weeks 90 participants Proportion achieving an permuted block method at and binary outcomes discontinued: Investigator Global baseline in a 2:1:2 ratio to with Cochran-Mantel- - Up to week 16: Assessment score of guselkumab 100 mg at week 0, 4, Haenszel Chi-square - Adalimumab 10 (2 adverse events, 1 cleared or minimal 12, and every 8 weeks through stratified by site, lack of efficacy, 4 patient withdrawal, 1 Version Page 19 of 79

84 Trial identifier Primary and secondary outcomes disease (0 or 1) and 90% improvement in PASI from baseline (PASI 90) were coprimary endpoints. Secondary outcomes: IGA, PASI, scalp specific Investigator Global Assessment, fingernail PGA, NAPSI, PGA of hands and/or feet, DLQI, Psoriasis Symptoms and Signs Diary, Safety, Antibodies. Randomisation and blinding week 44; placebo at week 0, 4, and 12 followed by guselkumab 100 mg at week 16 and 20, and every 8 weeks through week 44; or adalimumab 80 mg at week 0, 40 mg at week 1, and 40 mg every 2. week through week 47. Central randomization was implemented using an interactive web response system. To maintain the blind, matching placebos were used. Subgroup analyses planned Statistical analysis continuous outcomes by ANCOVA with site as a covariate. All statistical analysis was 2-sided with alpha Analyses tested in a fixed sequence to control for multiplicity. Data management: - details of patient withdrawals - missing data imputation lost to follow-up, 1 treatment noncompliance, 1 protocol violation) - Guselkumab 7 (4 adverse events, 1 lost to follow-up, 2 treatment noncompliance) - Placebo 7 (2 adverse events, 2 lack of efficacy, 2 patient withdrawal, 1 lost to follow-up) - from cross over to week 48: - adalimumab 42 (9 adverse events, 11 lack of efficacy, 10 patient withdrawal, 5 lost to follow-up, 3 treatment noncompliance, 1 pregnancy, 3 other) - continued guselkumab 21 (6 adverse events, 3 lack of efficacy, 4 patient withdrawal, 2 lost to follow-up, 3 treatment non-compliance, 1 protocol violation, 2 other) - crossed to guselkumab 2 did not cross over, 3 discontinued (1 adverse event, 1 patient withdrawal, 1 lost to follow-up) Missing values were considered nonresponders for binary endpoints or had baseline values carried forward for continuous endpoints for those who discontinued for lack of efficacy or an adverse event of worsening psoriasis, or who started a protocol-prohibited treatment. Others were considered non-responders for binary endpoints and last observation carried forward for continuous endpoints. Placebo: 15 (adverse events 2; lack of efficacy 4; lost to follow up 1; VOYAGE 2 [5] Primary outcomes: Patients were randomized NR Coprimary outcomes Coprimary end points 2:1:1 using a permuted block and binary outcomes were proportion of method at baseline to guselkumab with Cochran-Mantel- Version Page 20 of 79

85 Trial identifier Primary and secondary outcomes patients achieving IGA 0/1 and PASI 90 by week 16 Secondary outcomes: Week 24: Proportion of patients achieving IGA 0, IGA 0/1, PASI 90, or PSSD symptom score 0 Week 24-48: The time to loss of PASI 90 response Week 16: Change from baseline in DLQI score, proportion of patients achieving IGA 0/1, PASI 90, PASI 75, ss-iga 0/1, and change from baseline in PSSD symptom score Randomisation and blinding 100 mg at week 0, 4, 12, and 20; placebo at week 0, 4, and 12, then guselkumab at week 16 and 20; or adalimumab 80 mg at week 0, 40 mg at week 1, and every 2. week thereafter through week 23. Central randomization was implemented using an interactive web response system. To maintain the blind, both guselkumab and adalimumab placebos were administered as necessary. Subgroup analyses planned Statistical analysis Haenszel Chi-square stratified by site, continuous outcomes by ANCOVA with site as a covariate. All statistical analysis was 2-sided with alpha Data management: - details of patient withdrawals - missing data imputation withdrawal by subject 7; protocol violation 1) Guselkumab: 18 (adverse events 9; lost to follow up 3; withdrawal by subject 1; protocol violation 3; non-compliance 1; other 1) Adalimumab: (adverse events 4; lack of efficacy 2; lost to follow up 2; protocol violation 1; non-compliance 2) Patients who discontinued treatment due to lack of efficacy or an adverse event of worsening of psoriasis, or started a protocol-prohibited medication/ therapy to improve psoriasis were considered treatment failures. Patients meeting treatment failure criteria before week 16 and patients not returning for week-16 evaluation were considered nonresponders for the week-16 primary end point. To control the overall type 1 error rate, the primary and major secondary analyses were tested in a fixed sequence, with the first major secondary end point tested only if the co-primary end points were met, and the subsequent end point(s) tested only if the preceding end point in the sequence was met. Ohtsuki 2018 Co-primary end-points Eligible patients were randomized NR Co-primary endpoints Patients who discontinued the study [6] were the proportion of (1:1:1) to guselkumab 50 mg, 100 were assessed drug because of lack of efficacy, a TEAE patients achieving an mg or placebo, with s.c. injections in a multiplicity- of worsening psoriasis or starting a Version Page 21 of 79

86 IGA cleared/minimal (0/1) and PASI-90 response ( 90% improvement in PASI from baseline) at week 16. Secondary end-points: Proportion of patients who achieved a PASI-75 response at week 16 Change from baseline in the Dermatology Life Quality Index (DLQI) score at week 16 Proportion of patients with IGA 0, IGA 0/1, PASI-50, PASI-75, PASI-90 and PASI-100 at week 16 and through to week 52 Change and % improvement in NAPSI score from baseline Proportion of patients who had a scalp-specific Investigator s Global Assessment (ss-iga) score of 0 or 0/1 who had a baseline score of 2 or more Proportion of patients who achieved a DLQI score of 0 or 1 (among patients with a at weeks 0, 4, and every 8 weeks (q8w) thereafter. Patients receiving placebo were crossed over to receive (1:1) guselkumab 50 mg or 100 mg at week 16 and 20 and every q8w thereafter. Randomization was performed centrally using a computergenerated randomization scheme, balanced using randomly permuted blocks and stratified by presence of PsA. Study site personnel, investigators and patients were blinded to treatment allocation until week 52 database lock. adjusted, fixedsequence testing procedure. Except for PsA, binary efficacy end-points at week 16 (e.g. co-primary endpoints) were analyzed using Fisher s exact test; continuous efficacy end-points at week 16 were evaluated using ANCOVA with treatment as a factor and baseline as a covariate; categorical efficacy end-points at week 16 with two or more levels were analyzed using the Cochran Mantel Haenszel test. protocol- prohibited psoriasis treatment were considered nonresponders for binary end-points or had baseline values carried forward for continuous endpoints. Last observation was carried forward for other patients with missing data. Safety analyses included all patients receiving one or more study drug administration and were summarized by actual treatment received. Version Page 22 of 79

87 Trial identifier Primary and secondary outcomes Randomisation and blinding Subgroup analyses planned Statistical analysis Data management: - details of patient withdrawals - missing data imputation baseline DLQI score of >1) Proportion of patients who achieved a reduction of 5 or more in the DLQI score from baseline Changes from baseline in the EQ-5D and physical and mental component scores of the SF-36 were assessed through week 48 AE- adverse event; DLQI- Dermatology quality of life index; IGS- investigators global assessment; IV- intravenous; NAPSI- nail psoriasis severity index; NR- not reported; PASI- Psoriasis Area Sensitivity Index; PGA- physicians global assessment; PSSD- psoriasis signs and symptoms diary Version Page 23 of 79

88 TABLE 5.3: PARTICIPANTS BASELINE CHARACTERISTICS Trial identifier ReSURFACE 1 [3] ReSURFACE 2 [3] VOYAGE 1 [4] Intervention Number of patients randomised Geography Age Mean (SD) years Female Number (%) Tildrakizumab mg Australia, Canada, Tildrakizumab 309 Japan, the 100mg UK, and the USA 46.9 (13.2) 46 4 (13 1) 82 (26.6) 102 (33.0) Placebo (13 5) 55 (35.5) Tildrakizumab 200mg Tildrakizumab 100mg Etanercept 50mg BIW for 12 weeks then QW (13 6) 89 (28.3) 307 Europe, Israel, and 44 6 (13 6) 87 (28.3) the 313 USA 45 8 (14 0) 91 (29.1) Placebo (12 2) 44 (28.2) Guselkumab 100mg Q8W Adalimumab 40mg Q2W VOYAGE 2 [5] Placebo Australia, Canada, Germany, Hungary, Korea, Republic of, Poland, Russian Federation, Spain, Taiwan, USA 43.9 (12.74) 42.9 (12.58) 89 (27.1) 85 (25.4) Placebo (12.9) 55 (31.6) Australia, Canada, Czechia, 43.3 (12.4) 75* (30.2)* Version Page 24 of 79 Ethnicity White: 209 (68%) Asian: 83 (27%) Other: 16 (5%) White: 217 (70%) Asian: 70 (23%) Other: 22 (7%) White: 101 (65%) Asian: 42 (27%) Other: 12 (8%) White: 284 (90%) Asian: 14 (4%) Other: 16 (5%) White: 279 (91%) Asian: 9 (3%) Other: 19 (6%) White: 289 (92%) Asian: 10 (3%) Other: 14 (4%) White: 144 (92%) Asian: 3 (2%) Other: 9 (6%) Caucasian: 262 (79.6) Black: 6 (1.8) Asian: 51 (15.5) Caucasian: 277 (82.9) Black: 8 (2.4) Asian: 47 (14.1) Caucasian: 145 (83.3) Black: 3 (1.7) Asian: 23 (13.2) White: 206 (83.1) Asian: 27 (10.9) Black: 8 (3.2) Weight - kg Mean (SD) BMI Mean (SD) (24 09) NR (23 87) NR (26 04) NR (21 23) NR (22 12) NR (21 48) NR (22 73) NR NR 29.7 (6.22) NR 29.8 (6.48) NR 28.9 (6.89) NR 29.6 (6.6)

89 Trial identifier Intervention Guselkumab 100mg Q8W Adalimumab, 40mg Q2W Number of patients randomised Geography Age Mean (SD) years Female Number (%) Germany, Korea, Poland, Russian Federation, Spain, USA 43.7 (12.2) 43.2 (11.9) 147* (29.6)* 78* (31.5)* Ethnicity White: 408 (82.3) Asian: 72 (14.5) Black: 6 (1.2) White: 200 (80.6) Asian: 37 (14.9) Black: 5 (2.0) Weight - kg Mean (SD) BMI Mean (SD) NR 29.6 (6.5) NR 29.6 (6.6) Placebo (10.56) 10* (15.6)* NR but narrative states (14.01) (4.791) Ohtsuki 2018 [6] Guselkumab 100mg Japan all patients were (11.07) 16* (25.4)* Q8W Japanese (16.04) (5.032) BIW- twice a week; NR- not reported; PASI- Psoriasis Area Sensitivity Index; QW- once a week; Q2W- every 2 weeks; Q8W- every 8 weeks; SD- standard deviation; USA- United States of America Version Page 25 of 79

90 TABLE 5.3 PARTICIPANTS BASELINE CHARACTERISTICS. CONTINUED Trial identifier ReSURFACE 1 [3] ReSURFACE 2 [3] VOYAGE 1 [4] VOYAGE 2 [5] Ohtsuki 2018 [6] Intervention Tildrakizumab 200mg Tildrakizumab 100mg Number of patients randomised Disease duration Years Mean (SD) PASI Mean (SD) DQLI Mean (SD) Previously treated with biologics (%) 308 NR 20.7 (8.51) 13.2 (6.87) 23% 309 NR 20.0 (7.85) 13.9 (6.68) 23% Placebo 155 NR 19.3 (7.07) 13.2 (7.25) 23% Tildrakizumab 200mg Tildrakizumab 100mg Etanercept 50mg BIW for 12 weeks then QW 314 NR 19.8 (7.52) 13.2 (7.03) 12% 307 NR 20.5 (7.63) 14.8 (7.24) 13% 313 NR 20.2 (7.36) 14.5 (7.20) 12% Placebo 156 NR 20 (7.57) 13.7 (6.98) 13% Guselkumab 100mg Q8W Adalimumab 40mg Q2W (12.27) 22.1 (9.49) 14.0 (7.48) 21.6% (11.27) 22.4 (8.97) 14.4 (7.29) 21.0% Placebo (12.44) 20.4 (8.74) 13.3 (7.12) 19.5% Placebo (11.9) 21.5 (8.0) 15.1 (7.2) 21.8% Guselkumab 100mg Q8W Adalimumab, 40mg Q2W Placebo 64 Guselkumab 100mg Q8W (12.0) 21.9 (8.8) 14.7 (6.9) 20.4% (11.7) 21.7 (9.0) 15.0 (6.9) 19.8% (10.291) (12.34) 10.6 (7.74) 15.6% (9.227) (12.19) 10.3 (7.27) 17.5% Version Page 26 of 79

91 5.1.2 Results per study Table 5.4 through Table 5.8 below display number of events and number of subjects by arm and by study as reported. The rate of events has been calculated from number of events and number of subjects. For all outcomes, the number of patients randomized to the treatment arm at baseline was used for calculating rates to form rates for the ITT population. The 95% CI has been calculated using the Clopper-Pearson method. Relative rates were calculated for the active arm relative to placebo. None of the trials had placebo control for more than 16 weeks. Number of events for the placebo arm at week was applied at week analysis to form relative rates. This alternative was deemed the most appropriate, since efficacy endpoints appear unlikely to significantly increase with placebo beyond week 12 (i.e. curve for PASI change from baseline becomes horizontal before week 12 see for instance Saurat et al. (2008)[10]. For consistency purposes and lack of a better alternative, an identical approach was taken for safety endpoints as well. The number of patients with a least one SAE during week 0-28 was not available from the resurface studies. The number of events were calculated as the sum of patients with at least one event during week 0-16 and patients with a least one event during week Patients with a SAE in both timeperiods will be double counted using this method. Number of patients with DLQI 0 or 1 was based on number reported. In the VOYAGE trials, it is stated that patients reporting DLQI of 0 or 1 at baseline were excluded from the DLQI response analyses [4, 5, 6 ]. This means that some patients in the ITT population may not have contributed to the number of events. However, it is important to note that when comparing the different DLQI populations (at baseline, for DLQI 0/1, and for mean change from baseline) the majority of patients excluded from the DLQI 0/1 analysis must actually have had missing baseline values. Therefore, Almirall chose to base the primary DLQI 0/1 analysis on the ITT population for both treatments. In a sensitivity analysis, the indirect comparison of DLQI 0/1 response rates were based on the analysis population applied in the publications (all patients with DLQI data available at base-line and for the guselkumab studies also with baseline DLQI score above 1) see Appendix F. Version Page 27 of 79

92 Tildrakizumab trials TABLE 5.4: OUTCOMES IN RESURFACE 1 Outcomes at week 12 Outcome Treatment Number of events Number of patients Rate of events 95% CI RR 95% CI PASI75 Placebo (0.03, 0.11) (5.88, 20.00) PASI90 SAE DLQI 0/1 Discontinuation Outcomes at week 28 Outcome Tildrakizumab 100mg (0.58, 0.69) Placebo (0.01, 0.06) (5.00, 33.33) Tildrakizumab 100mg (0.29, 0.40) Placebo (0.00, 0.04) 2.50 (0.30, 20.00) Tildrakizumab 100mg (0.01, 0.04) Placebo (0.02, 0.10) 7.69 (4.00, 16.67) Tildrakizumab 100mg (0.35, 0.46) Placebo (0.03, 0.11) Tildrakizumab 100mg (0.01, 0.05) Treatment Number of events Number of patients Rate of events 0.50 (0.20, 1.23) 95% CI RR 95% CI PASI75 PASI90 SAE* Placebo (0.03, 0.11) (6.67, 25.00) Tildrakizumab 100mg (0.69, 0.79) Placebo (0.01, 0.06) (7.14, 50.00) Tildrakizumab 100mg (0.42, 0.53) Placebo (0.00, 0.04) 5.56 (0.72, 50.00) Tildrakizumab 100mg (0.02, 0.06) DLQI 0/1 Placebo (0.02, 0.10) (4.76, 20.00) Tildrakizumab 100mg (0.43, 0.55) Placebo (0.03, 0.11) Discontinuation 6.67 (3.85, 11.11) Tildrakizumab 100mg (0.10, 0.18) * Number of patients with at least one SAE at week 28 is estimated as the reported number of patients with a least one event during week 0-16 plus the number of patients with at least one event during week Patients with an SAE during both time-frames will be double-counted Version Page 28 of 79

93 TABLE 5.5: OUTCOMES IN RESURFACE 2 Outcomes at week 12 Outcome Treatment Number of events Number of patients Rate of events 95% CI RR 95% CI PASI75 PASI90 SAE Placebo (0.03, 0.11) (5.56, 20.00) Tildrakizumab 100mg (0.56, 0.67) Placebo (0.00, 0.05) (7.69, ) Tildrakizumab 100mg (0.33, 0.44) Placebo (0.01, 0.06) 0.51 (0.13, 2.00) Tildrakizumab 100mg (0.00, 0.03) DLQI 0/1 Discontinuation Outcomes at week 28 Outcome Placebo (0.04, 0.13) 5.00 (2.86, 9.09) Tildrakizumab 100mg (0.33, 0.44) Placebo (0.05, 0.15) Tildrakizumab 100mg (0.02, 0.07) Treatment Number of events Number of patients Rate of events 0.43 (0.21, 0.92) 95% CI RR 95% CI PASI75 PASI90 SAE* Placebo (0.03, 0.11) (6.25, 25.00) Tildrakizumab 100mg (0.65, 0.75) Placebo (0.00, 0.05) (10.00, 100.0) Tildrakizumab 100mg (0.47, 0.58) Placebo (0.01, 0.06) 1.64 (0.55, 5.00) Tildrakizumab 100mg (0.02, 0.07) DLQI 0/1 Placebo (0.04, 0.13) 6.67 (3.85, 11.11) Tildrakizumab 100mg (0.45, 0.57) Placebo (0.05, 0.15) Discontinuation 0.65 (0.33, 1.28) Tildrakizumab 100mg (0.04, 0.09) * Number of patients with at least one SAE at week 28 is estimated as the reported number of patients with a least one event during week 0-16 plus the number of patients with at least one event during week Patients with an SAE during both time-frames will be double-counted Version Page 29 of 79

94 Guselkumab trials TABLE 5.6: OUTCOMES IN VOYAGE 1 Outcomes at week 16 Outcome Treatment Number of events Number of patients Rate of events 95% CI RR 95% CI PASI75 Placebo (0.03, 0.10) (8.33, 33.33) PASI90 Guselkumab 100mg (0.88, 0.94) Placebo (0.01, 0.07) Guselkumab 100mg (0.68, 0.78) (11.11, 50.00) SAE Placebo (0.00, 0.05) 1.41 (0.38, 5.26) Guselkumab 100mg (0.01, 0.05) DLQI 0/1* Discontinuation Outcomes at week Outcome PASI75 (week 24) PASI90 (week 24) Placebo (0.02, 0.08) (6.67, 25.00) Guselkumab 100mg (0.49, 0.60) Placebo (0.02, 0.08) Guselkumab 100mg (0.01, 0.04) Treatment Number of events Number of patients Rate of events 0.53 (0.19, 1.49) 95% CI RR 95% CI Placebo (0.03, 0.10) (8.33, 33.33) Guselkumab 100mg (0.88, 0.94) Placebo (0.01, 0.07) (11.11, 50.0) Guselkumab 100mg (0.76, 0.84) SAE Placebo N/A N/A N/A N/A N/A N/A Guselkumab 100mg N/A N/A N/A N/A DLQI 0/1* Placebo (0.02, 0.08) (6.67, 25.00) Guselkumab 100mg (0.54, 0.65) Placebo N/A N/A N/A N/A Discontinuation Guselkumab 100mg N/A N/A N/A N/A * Patients with DLQI of 0 at baseline was excluded in the response analysis reported in [4] N/A N/A Version Page 30 of 79

95 TABLE 5.7: OUTCOMES IN VOYAGE 2 Outcomes at week 16 Outcome Treatment Number of events Number of patients Rate of events 95% CI RR 95% CI PASI75 PASI90 SAE Placebo (0.05, 0.12) (7.14, 16.67) Guselkumab 100mg (0.83, 0.89) Placebo (0.01, 0.05) (12.50, 50.0) Guselkumab 100mg (0.66, 0.74) Placebo (0.00, 0.03) 1.33 (0.36, 5.00) Guselkumab 100mg (0.01, 0.03) DLQI 0/1 Discontinuation Outcomes at week Outcome Placebo (0.01, 0.06) (7.69, 33.33) Guselkumab 100mg (0.47, 0.56) Placebo (0.03, 0.10) Guselkumab 100mg (0.02, 0.06) Treatment Number of events Number of patients Rate of events 0.60 (0.31, 1.18) 95% CI RR 95% CI PASI75 (week 24) PASI90 (week 24) SAE (week 28) Placebo (0.05, 0.12) (7.14, 16.67) Guselkumab 100mg (0.86, 0.92) Placebo (0.01, 0.05) (14.29,100.0) Guselkumab 100mg (0.71, 0.79) Placebo (0.00, 0.03) 3.03 (0.89, 10.00) Guselkumab 100mg (0.02, 0.06) DLQI 0/1* (week 28) Placebo (0.01, 0.06) (9.09, 33.33) Guselkumab 100mg (0.53, 0.61) Discontinuation (week 28) Placebo Guselkumab 100mg (0.03, 0.10) (0.03, 0.08) * Patients with DLQI of 0 at baseline was excluded in the response analysis reported in [5] 0.87 (0.47, 1.61) Version Page 31 of 79

96 TABLE 5.8: OUTCOMES IN OHTSUKI 2018 Outcomes at week 16 Outcome Treatment Number of events Number of patients Rate of events 95% CI RR 95% CI PASI75 PASI90 SAE DLQI 0/1 Placebo (0.02, 0.15) (5.26, 33.33) Guselkumab 100mg (0.73, 0.92) Placebo (0.00, 0.06) (5.56, inf) Guselkumab 100mg (0.57, 0.81) Placebo (0.00, 0.11) 0.51 (0.05, 5.56) Guselkumab 100mg (0.00, 0.09) Placebo (0.02, 0.15) (4.00, 25.00) Guselkumab 100mg (0.52, 0.77) Placebo (0.10, 0.30) Discontinuation Guselkumab 100mg (0.00, 0.09) * Patients with DLQI of 0 at baseline was excluded in the response analysis reported in [6]. Abbreviations: inf: infinite Comparative analyses Methods applied in quantitative syntheses 0.08 (0.01, 0.63) Risk ratios In order to compare tildrakizumab 100mg and guselkumab 100mg, a Bucher [11] indirect comparison has been calculated using placebo as common comparator. This involves three steps for each endpoint separately: (1) Pairwise meta-analysis of placebo and tildrakizumab to estimate a risk ratio (2) Pairwise meta-analysis of placebo and guselkumab to estimate a risk ratio (3) Combining risk ratios obtained in (1) and (2) to estimate a risk ratio of tildrakizumab and guselkumab Step 1 and 2 were originally conducted with placebo as point of origin whereas step 3 originally was conducted with guselkumab as the point of origin. Values provided throughout this document have been inverted to reflect analyses with active treatment (step 1 and 2) and tildrakizumab (step 3) as the points of origin. Please note that all forest plots presented in Appendix B originate from the original analysis and therefore have placebo as the point of origin. Risk ratios can vary by study. If they vary considerably, the pairwise meta-analyses need to be performed using a random effects (RE) model. Otherwise, a fixed effect (FE) model may be used. It needs to be noted, though, that it is very difficult to estimate variations in-between studies if only a small number of studies are considered, as is the case here. Heterogeneity is the term used to describe variability in intervention effects among studies due to clinical and/or methodological differences. It can be quantified through the use of the I 2 statistic. This statistic provides an estimate of the percentage of the variability in effect estimates that is due to heterogeneity rather than chance. The Cochrane Handbook [12] suggests I 2 values between 0% and 40% may not be important, and those between 30% and 60% may represent moderate heterogeneity. To assess heterogeneity, I 2 statistics have been calculated for each pairwise comparison. Version Page 32 of 79

97 If a comparison was reported by one study only, then no meta-analysis was undertaken. In this case, the risk ratio which was taken for step 3 above was identical to the one reported by the single study. Results for both FE and RE models have been produced. No adjustments for multiplicity have been made, and all risk ratios are reported with their 95% confidence interval. Absolute risk reductions Absolute risk reductions (ARR) in % points were calculated based on observed results of guselkumab arms and relative risk ratios obtained as described above. The following steps were undertaken: 1. If PR denotes the assumed proportion of events for tildrakizumab 100mg, then: PR = sum of all events in tildrakizumab 100mg arms across all studies sum of all subjects in tildrakizumab 100mg arms across all studies 2. If RR denotes the risk ratio of tildrakizumab 100mg to guselkumab 100mg as obtained before, and ARR denotes the absolute risk reduction, then: ARR = (RR 1) PR To estimate 95% confidence interval for ARR, the ARR at the confidence limits for RR was calculated using the formula above but assuming that the proportion of patient with events (PR) is constant, i.e., ignoring the sample variation in this estimate. Results compared at week Forest plots to illustrate the results of the pairwise meta-analyses are presented in Appendix B. Apart from discontinuations, heterogeneity was very low. The following table displays the I 2 statistics for each direct comparison by PASI level. Note that there are no I 2 statistics for SAE and discontinuations for the comparison of placebo and guselkumab 100mg. The reason is that only one study reported these outcomes, and therefore no meta-analysis was undertaken. TABLE 5.9: HETEROGENEITY ASSESSMENT RESULTS, WEEK Treatment 1 Treatment 2 I 2 PASI 75 Placebo Tildrakizumab 100mg 0.0% Placebo Guselkumab 100mg 0.0% PASI 90 Placebo Tildrakizumab 100mg 0.0% Placebo Guselkumab 100mg 0.0% SAE Placebo Tildrakizumab 100mg 3.9% Placebo Guselkumab 100mg NA DLQI 0/1 Placebo Tildrakizumab 100mg 0.0% Placebo Guselkumab 100mg 0.0% Discontinuations Placebo Tildrakizumab 100mg 84.5% Placebo Guselkumab 100mg NA DLQI- Dermatology Life Quality Index; NA- not applicable; PASI- Psoriasis Area Sensitivity Index; SAE- Serious Adverse Events Version Page 33 of 79

98 The high amount of heterogeneity for discontinuations appears to have its origins in a low number of discontinuations for tildrakizumab in the Re-SURFACE 2 study. For this endpoint, the RE model should be considered. For all the other models the FE model appears to be appropriate. For PASI 75, the risk ratios for guselkumab to tildrakizumab obtained by both models are equal to 1, which signifies that the same number of events are observed for both treatments. For PASI 90, the risk ratios are below 1, favouring guselkumab 100mg, but the 95% CIs do contain 1. Thus, it could not be demonstrated that the two treatments are different for PASI levels 75 and 90. Regarding SAE, the risk ratios calculated by both models are below 1, which means that more SAEs were observed for guselkumab 100mg. However, the result is again not statistically significant since the 95% CIs contain 1. For DLQI 0/1, both models calculated the risk ratios as below 1, favouring guselkumab 100mg. The result is statistically significant since the CIs do not contain 1. The statistically significant difference in DLQI 0/1 response rate is largely driven by a substantially higher placebo response in the resurface trials (especially resurface 2) than VOYAGE trials. In the resurface 1 and 2 the placebo response was 5 % and 8 % respectively, compared to only 4 % and 3 % in VOYAGE 1 and 2, respectively. This is in contrast to placebo PASI response rates which seem similar across trials. The absolute difference (calculated from overall results in the VOYAGE trials and estimated RR from the Bucher analysis) is 57.9% but with very wide confidence intervals (4.8% to 43.8%) including the MCID set by the Medicine Council indicating that the added clinical value of this finding is uncertain. Regarding discontinuations, both models return a risk ratio above 1, which signifies that more discontinuations are estimated to happen for treatments with tildrakizumab 100mg. However, the findings are not statistically significant, since the 95% CIs contain 1. Details of the risk ratios are displayed in the table below. Version Page 34 of 79

99 TABLE 5.10: SUMMARY OF THE RESULTS OF THE BUCHER METHOD, WEEK PASI 75 PASI 90 SAE Outcome DLQI 0/1 Discontinuations Studies included in the analysis resurface 1+2 VOYAGE 1+2 resurface 1+2 VOYAGE 1+2 resurface 1+2 VOYAGE 2 resurface 1+2 VOYAGE 1+2 resurface 1+2 VOYAGE 2 Fixed/ random effects Tildrakizumab (100 mg) to placebo Risk ratio (95% CI) Guselkumab (100mg) to placebo Tildrakizumab (100 mg) to guselkumab (100 mg) FE 12.5 (7.69, 20.0) 12.5 (9.09, 6.67) 1.00 (0.57, 1.75) RE 12.5 (7.69, 20.0) 12.5 (9.09,16.67) 1.00 (0.57, 1.75) FE 25 (11.11, 50) (16.67,50.0) 0.81 (0.30, 2.17) RE 25 (11.11, 50) (16.67,50.0) 0.81 (0.30, 2.17) FE 2.17 (0.82, 5.88) 3.03 (0.89, 10.0) 0.72 (0.15, 3.45) RE 2.22 (0.81, 5.88) 3.03 (0.89, 10.0) 0.74 (0.15, 3.57) FE 7.69 (5, 12.5) (10.0, 25.0) 0.47 (0.24, 0.92) RE 7.69 (5, 12.5) (10.0, 25.0) 0.47 (0.24, 0.92) FE 1.19 (0.74, 1.92) 0.87 (0.47, 1.61) 1.39 (0.63, 3.03) RE 1.22 (0.36, 4.17) 0.87 (0.47, 1.61) 1.41 (0.36, 5.56) Absolute effect comparator 89.90% 77.20% Absolute effect estimate CI- confidence interval; DLQI- Dermatology Life Quality Index; FE- fixed effects; PASI- Psoriasis Area Sensitivity Index; RE- random effects; SAE- Serious Adverse Events * Positive numbers imply more events are predicted for patients treated with tildrakizumab 100mg, compared to those treated with guselkumab 100mg. 3.60% 57.90% 2.90% Estimated risk difference* (95% CI) 0.0% 0.0% -14.4% -14.4% -1.0% -1.0% -30.6% -30.6% 1.1% 1.2% (-38.8%, 67.8%) (-38.8%, 67.8%) (-53.9%, 90.6%) (-53.9%, 90.6%) (-3.0%, 8.8%) (-3.1%, 9.3%) (-43.8%, -4.8%) (-43.8%, -4.8%) (-1.1%, 5.9%) (-1.9%, 13.2%) Version Page 35 of 79

100 Appendix G presents the analysis of DLQI response rate based on the analysis population in the original publications. The conclusion of this analysis is the same as above; the confidence interval for the RR does not include 1 but the confidence interval for ARR includes the protocol-defined MCID. Importantly DLQI 0/1 response rates only assess one tail of the entire DLQI data distribution (score range from 0-30), and thus if the two distributions are not completely analogous, DLQI 0/1 data may not capture the full extent of the relationship between the two treatment. Alternatively, the effect on DLQI could be assessed by a mean of the distribution, for which mean change from baseline appears the most appropriate measure of treatment effect. This sensitivity analysis is provided in appendix E. The analysis of change from baseline to week (see Table 5.11) showed that the treatment effect on this parameter is similar for guselkumab 100mg and tildrakizumab 100mg. The change from baseline to week for guselkumab 100mg compared to tildrakizumab 100mg was points (95%CI: -2.86, 1.46). This analysis supports that no significant or clinical important difference is to be expected on patient quality of life for patients treated with tildrakizumab 100mg compared to patient treated with guselkumab 100mg. TABLE 5.11 RESULT OF BUCHER INDIRECT COMPARISON. MEAN DIFFERENCE IN DLQI CHANGE FROM BASELINE TO WEEK Tildrakizumab 100mg compared to guselkumab 100mg Mean difference 95% CI In addition to the results presented here, results have been estimated using indirect comparison of resurface and VOYAGE trials at week (appendix C) and in a sensitivity analysis including also the Ohtsuki trial trial of guselkumab [6] in a Japanese population (appendix D). These analyses yielded identical findings. The overall conclusion of all three indirect comparison is that there was no statistically significant difference between guselkumab and tildrakizumab for PASI 75, PASI 90, SAE and rate of discontinuations at either timepoint. For DLQI 0/1 the risk ratios were statistically significant in favour of guselkumab. Thus, for all critical endpoints (PASI 75 and SAEs) and all but one important endpoint no difference was detected between the two treatments. Narrative comparison of outcomes after one year of treatment Trial period, trial geography, patient flow, and patient baseline characteristics are detailed in section 4.2, and as it can be seen here, the two resurface and VOYAGE trials appear comparable regarding these characteristics. Details on trial design for each of these four trials can be found in section 4.2. At week 28 in the resurface trials, patients on either dose of tildrakizumab who were PASI 75 or PASI 50 responders were re-randomized to either their existing tildrakizumab dosing regimen, the alternative dose of tildrakizumab or placebo (options varied between the two treatment arms and Version Page 36 of 79

101 trials - see 4.2 for details). Non-responders were discontinued from their respective trial. Using a similar concept, PASI 90 responders on guselkumab were re-randomized to either their existing treatment or placebo at week 28 in the VOYAGE 2 trial (see 4.2 for details), whereas non-responders were switched to guselkumab 100 mg Q8W. In the VOYAGE 1 trial, no re-randomization was conducted throughout the trial (see 4.2 for details). These major trial design differences significantly obscure narrative comparison of tildrakizumab and guselkumab for most outcomes after one year of treatment. An examination of complications for each outcome is provided below: - PASI response rates: Due to the re-randomization at week 28 in the resurface trials, it is not possible to calculate response rates for the ITT population after one year of tildrakizumab treatment, and therefore, one-year data from these studies cannot be compared to VOYAGE 1 during which patients continue the same treatment throughout one year. Moreover, since responders at week 28 are defined differently in the resurface trials (PASI75) compared to VOYAGE 2 (PASI90), a direct comparison between response rates from these trials is not meaningful. A general comparative description of maintenance of response for the resurface trials and the VOYAGE 2 trial until one year of treatment may however provide some value and is provided below. - DLQI 0/1 response rates: Any meaningful comparison is not possible due to the same argumentation as above for PASI response rates. - SAE: Given the assumption that risk of SAE is largely independent of study design as long the target population and dosing regimen is constant, it seems possible to narratively compare the two treatments on this outcome throughout one year of therapy. - Discontinuation rate: Since non-responders (< PASI 50) are discontinued at week 28 in the resurface trials in contrast to VOYAGE 2, during which all patients continue the trial, comparison of discontinuation data after one year of treatment is not relevant. Comparative description of maintenance of response throughout one year of treatment Data for PASI 75 responders on tildrakizumab 100 mg Q12W, who continued their treatment in part 3 of the resurface trials, are depicted in Figure 5.5. In resurface 1, 85 % of patients, who obtained a PASI 75 response on tildrakizumab 100 mg and continued their treatment in part 3, maintained their PASI 75 response at the end of part 3 (i.e. week 64; non-responder imputation). At the end of part 3 (i.e. week 52) of resurface 2, 90 % of PASI 75 responders, who continued on tildrakizimab 100 mg, sustained their response (non-responder imputation; [3]). Thus, approximately 9 out of 10 patients on tildrakizumab 100 mg appear to maintain a highly clinically meaningful response (PASI 75) over a period of half a year. Version Page 37 of 79

102 FIGURE 5.5 PASI 75 RESPONSE OVER TIME IN WEEK 28 PASI 75 RESPONDERS WHO CONTINUED TILDRAKIZUMAB 100 MG Non-responder imputation. Source: Adapted from [3] At week 28, 65 % and 74 % of the PASI 75 responders, who continued tildrakizumab 100 mg, were also PASI 90 responders in resurface 1 and 2, respectively. Of these PASI 75 responders, 56 % and 75 % had a PASI 90 response at the end of part 3 of resurface 1 and 2, respectively (see Figure 5.6; non-responder imputation; Almirall data on file). Thus, these data again substantiate that a clinical response on tildrakizumab 100 mg is largely maintained over time. FIGURE 5.6 PASI 90 RESPONSE OVER TIME IN WEEK 28 PASI 75 RESPONDERS WHO CONTINUED TILDRAKIZUMAB 100 MG Non-responder imputation. Source: Almirall data on file Among partial responders (i.e. > PASI50 but < PASI75) at week 28 in resurface 1 who continued on tildrakizumab 100 mg, 63 % enhanced their response to PASI75 on tildrakizumab 100 mg (non- Version Page 38 of 79

103 responder imputation; [3]). The corresponding figures for resurface 2 were 62 % on tildrakizumab 100 mg during part 3 (non-responder imputation; [3]). Thus, the skin symptoms of a substantial proportion of partial responders at week 28 continued to improve throughout one year of treatment. Data curve for PASI 90 responders on guselkumab 100 mg Q8W, who continued their treatment throughout week 48 of the VOYAGE 2 trial can be found in [5]. At week 48, 89.6 % of patients, who obtained a PASI 90 response on guselkumab 100 mg and continued their treatment, maintained their response[5]. In conclusion, in line with tildrakizumab results approximately 9 out of 10 patients on guselkumab 100 mg Q8W maintained a highly clinically meaningful response (PASI 90) over a period of half a year. However, this comparison should be interpreted with caution due to the difference in responder definition (PASI 75 versus PASI 90) as well as data endpoint (week 52/64 versus week 48). Narrative comparison of SAE rates At the cut-off for our literature search (20 th of November 2018), SAE rates after one year of treatment have not been reported in peer-reviewed manuscripts for the two resurface trials as well as the VOYAGE 2 trial. However, EMA s European public assessment report for either treatment provide SAE per 100 patient-years from a pooled safety analysis of relevant clinical trials. Data from the two VOYAGE trials were included in the analysis for guselkumab, whereas the analysis for tildrakizumab included the two resurface trials as well as a phase IIb study (NCT ) in the same target population [1, 13]. The inclusion of the phase IIb trial may appear confounding, but an unpublished analysis of data solely from the resurface trials return the exact same value as the analysis published in the EPAR for Ilumetri. For tildrakizumab, the SAE rate per 100 patient years was found to be 5.81 through the base period of the trials (week 64, 52 and 52 for resurface 1, resurface 2 and phase IIb, respectively) whereas the risk for guselkumab was 6.05 SAE per 100 patient years after 48 weeks of treatment [1, 13]. Thus, the risk of SAE appeared very low and similar for the two treatments throughout one year of therapy Subgroup analysis of Ilumetri trials Patients with failure on treatments with IL-12/23 target Ustekinumab (Stelara) is currently the only anti-psoriasis treatment available which inhibits the combination of IL-12 and IL-23 via the common p40 subunit (European marketing authorization since 15 th of January 2009[14]. In addition to tildrakizumab, the only other specific IL-23 (p19) inhibitor, guselkumab (Tremfya), obtained marketing authorization on the 9 th of November 2017[13]. The two resurface trials were conducted in the period between December 2012 to October 2015, which precludes patients that have failed on a IL-23p19 treatment to enter these trials [3]. Additionally, previous use of treatments targeting IL23 via the p40 or p19 subunit was a specific exclusion criterion for both the resurface 1 and resurface 2 trials [3]. Finally, no other trial investigating tildrakizumab in moderate to severe psoriasis has been conducted since the conclusion of the resurface trials. Hence, tildrakizumab efficacy/safety data for patients with a treatment failure on either ustekinumab or guselkumab are currently not available. Patients with failure on biologic therapy Both resurface 1 and 2 enrolled patients who had been exposed to previous biologic treatment (excluding p40 and p19 IL-23 as well as IL-17 antagonists; [3]). However, these patients had not necessarily experienced a failure on previous biologic treatment, and moreover, the clinical trial data do not allow for differentiation between patients who are true failures on previous biologic Version Page 39 of 79

104 treatment and patients who merely have been exposed to these drugs[3]. Thus, Table 5.12 shows PASI 90 response rates for patient who are naïve to biologics versus a group of biologic-experienced patients. As shown, no clinically relevant difference (i.e. Δ 15 %) was found between patients who are naïve to biologic therapy and biologic-exposed patients including an unknown number of patients that have actually failed on biologic treatment. TABLE 5.12: PASI 90 RESPONSE RATES FOR BIOLOGIC-NAIVE VERSUS BIOLOGIC-EXPOSED PATIENTS AT WEEK 12 AND WEEK 28 PASI 90 Biologic-exposed Biologic-naïve Absolute Δ 15 % response rates (n = 110) (n = 506) difference (Δ) Week (30.0 %) 193 (38.1 %) p.p. No Week (45.5 %) 258 (50.9 %) p.p. No Intention-to-treat population. Non-responder imputation. PASI- Psoriasis Area Sensitivity Index; p.p.- percentage points. Source: Almirall Data on file 6 Other considerations The Expert Committee for psoriasis has asked Almirall to provide additional information regarding a number of specific questions pertaining to the clinical use of tildrakizumab in a Danish setting. Almirall has attempted to address these very relevant questions using all available data, but given the current early stage of tildrakizumab s lifecycle, a proportion of the results cannot be expected to be published in peer-reviewed manuscripts. Possibility to pause treatment In the resurface 1 trial, PASI75 responders on tildrakizumab 100 mg were re-randomized to either placebo or continue their previous treatment. Thus, relapse data for the withdrawal group may provide insight to the possibility of treatment pause. Relapse was defined as loss of PASI 75 response, and as depicted in Figure 6.1, the median time to loss of PASI 75 response from rerandomization at week 28 was 142 days, which corresponds to 226 days since the last tildrakizumab dose of 100 mg [15]. At the end of part 3 (i.e. week 64), 54 % of participants in the withdrawal group had lost the PASI 75 response[15]. In comparison, only 15 % of patients who continued tildrakizumab 100 mg in to part 3 lost their PASI 75 response [3]. Version Page 40 of 79

105 FIGURE 6.1 TIME TO LOSS OF PASI 75 RESPONSE IN RESURFACE 1 AFTER RE-RANDOMIZATION TO PLACEBO AT WEEK 28 Relapse: Loss of PASI75 response. Last tildrakizumab dose administered at week 16 (12 weeks before). Source: Adapted from Thaci et al. (2018) [15] Alternatively, relapse may be defined as loss of more than 50 % of the achieved PASI improvement. With this alternative definition, the median time to relapse from re-randomization at week 28 was 226 days, which corresponds to 310 days since the last tildrakizumab dose of 100 mg [15]). Possibility of dose reduction of dose interval prolongation No data from the resurface trials exist on dose reduction from tildrakizumab 100 mg or dose interval prolongation. However, in a recent phase IIb trial (NCT ) patients who obtained a PASI 75 response at week 16 were re-randomized to continue tildrakizumab 100 mg Q12W or a dose of 25 mg Q12W. 97 % of the participants who continued the 100 mg dosing regimen maintained their response at week 52, which is statistically significantly (P < 0.005) superior to patients who underwent dose reduction to 25 mg (70 %)[16]. Elaboration on possibility to use 200 mg for patients with certain characteristics Overall, there are no discernable difference between the two doses of tildrakizumab regarding efficacy or safety for the general patient population included in the phase III trials. Therefore, the recommended dose for tildrakizumab is 100 mg at week 0, 4, and every 12 th week thereafter according to the SmPC of Ilumetri: Version Page 41 of 79

106 The recommended dose in adults is 100 mg by subcutaneous injection at weeks 0, and 4 and every 12 weeks thereafter. In patients with certain characteristics (e.g. high disease burden, body weight 90kg) 200 mg may provide greater efficacy. The term high disease burden is not clearly defined neither in the SmPC nor in the EPAR for Ilumetri. In the EPAR, high disease burden is mentioned in the context of a baseline PASI or BSA of more than 20. For the purpose of this discussion, we will focus on the PASI definition. There are no clinical pharmacology data to support the use of a higher dose in patients with higher baseline PASI, and pharmacology analysis do not provide a clear-cut argument for using 200 mg in patients with a body weight above 90 kg. For instance, EMAs EPAR for Ilumetri concludes that While the population PK analysis showed a slight decrease in exposure with increased body mass, increased tildrakizumab exposure was not linked to greater clinical response. However, There is a point that in lower weight patients < 90 kg the 100mg may be sufficient dose, as body weight was identified as most influential covariate on tildrakizumab PK. Supportively, from the pharmacokinetic point of view, subgroup analysis regarding covariate weight indicates that exposure in terms of steady state AUCss following 100 mg Q12W for patients 90 kg and following 200 mg Q12W for patients > 90 kg will be more balanced across the patient population. In addition to these clinical pharmacology data, unpublished post-hoc sub-analyses of efficacy endpoints (pooled analysis of both resurface trials) were considered during the decision process to include the possibility to use 200 mg for patients with high disease burden (baseline PASI > 20) and/or body weight > 90 kg in the SmPC. Figure 6.2 depicts various efficacy response rates over time by baseline PASI. For patients with a baseline PASI > 20 there might be a minor trend towards better efficacy for the 200 mg dose regarding stricter outcomes such as PASI 90 or 100 at week 28, but the absolute difference does not exceed 15 p.p. Moreover, these minor differences seem to more or less diminish at later time points. FIGURE 6.2 EFFICACY AT DIFFERENT TIME POINTS BY BASELINE PASI Version Page 42 of 79

107 Non-responder imputation. Pooled analysis from resurface 1 and 2. Source: Almirall data on file. Efficacy endpoints at different time points grouped by body weight is shown in Figure 6.3. At week 28, it is not possible to detect a tendency towards a better response of 200 mg in patients with a body weight of more than 90 kg compared to patient with a body weight less than 90 kg. There might be a minor trend towards better response to the 200 mg dose for patients above 90 kg at week 52, but at week 148, no apparent difference is evident. Version Page 43 of 79

108 FIGURE 6.3 EFFICACY AT DIFFERENT TIME POINTS BY BODY WEIGHT Non-responder imputation. Pooled analysis from resurface 1 and 2. Source: Almirall data on file. In conclusion, according to the criteria for added clinical value set in the Danish Medicine Council's protocol there is limited evidence for the difference between the two dosages. Therefore, Almirall recommends inclusion of the 100 mg dose as standard dosing option in the Danish national recommendations. Version Page 44 of 79

109 Relationship between loading dose and maintenance dose The optimal dose regimen selected for tildrakizumab was based on the phase II and III trial program, where it was clearly demonstrated that the recommended dose regimen (Week 0 and Week 4 followed with Q12W dosing thereafter) provided the best onset of action and efficacy during the induction and maintenance phases, respectively. Data from phase I [17] and phase II [16] trials and as well as PK/PD relationships based on a mean half-life of 23,4 days [1], showed that less frequent dossing (e.g. Weeks 0, 4 and 8; [17] yield a more rapid onset of activity. This supported the need for a loading dose at Week 4. Dosing frequency beyond 12 weeks was not expected to result in adequate levels to support sustained clinical response. The two phase III trials ratified the findings obtained in phase II. It should be noticed that the current dose regimen has been demonstrated to be optimal, efficacious and safe in the two phase III trials and that no such information is available for a less frequent schedule during the first 12 weeks of treatment. Given the long tildakizumab half-life (23,4 days; [1]) a relatively low maintenance dose is needed to keep serum concentrations at therapeutic levels (that is 100 mg QW12), however, this comes with the caveat that longer time is required to reach therapeutic level using a maintenance dosing regimen only. Therefore, considering the linear and time-independent pharmacokinetics of tildrakizumab [1], the administration of the second dose at approximately its half-life (that is, at week 4) is translated to a 2-fold increase in the peak plasma levels and, importantly, into trough concentrations (concentrations at the end of the dosing interval) similar to those of the steady state. Figure 6.4 below describes this well-known tildrakizumab PK profile (notice that Figure 6.4 corresponds to a dose of 200 mg, but the PK behaviors it is exactly the same for a 100 mg dose but with 2-fold lower concentrations). In summary, the Week 4 tidrakizumab dose followed with Q12W dosing thereafter, provide the best onset of action and efficacy during the induction and maintenance phases, respectively. Version Page 45 of 79

110 FIGURE 6.4 TILDRAKIZUMAB SERUM CONCENTRATION-TIME PROFILE FOR RESURFACE 1 Source: Almirall data on file. Blue line represent simulated concentrations after 200 mg at 0 and 4 followed by Q12W thereafter. Filled circles represent mean experimental concentration trough values found in psoriasis patients ( 90 kg) in resurface 1 at the same simulated doses. Maintenance of response between dosing every 12 weeks Insights to maintenance of response between doses of tildrakizumab 100 mg every 12 weeks may be uncovered by exploring long term efficacy data. Figure 6.5 depicts pooled PASI 75 and PASI 90 response rate from week 28 to week 148, and as also shown, tildrakizumab is dosed a week 28, 40, 52, 64, 76, 88, 100, 112, 124, 136, and 148 (purple arrows). The response rates appear to be largely maintained and, thus, there is no pattern of a decrease in response rates between doses[15] FIGURE 6.5 LONG-TERM PASI RESPONSE RATES THROUGH WEEK 148 No imputation of missing data. Pooled analysis from resurface 1 and 2. Adapted from [15] Version Page 46 of 79